Imidazole 5-position substituted angiotensin II antagonists

ABSTRACT

Novel substituted imidazoles of Formula (I), which are useful as angiotensin II antagonists, are disclosed: ##STR1##

This is a division of application Ser. No. 08/072,977, filed Jun. 10,1993, now U.S. Pat. No. 5,395,844.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to novel imidazole 5-position substitutedangiotensin II antagonists. The invention also relates to pharmaceuticalcompositions containing these novel imidazoles and pharmaceuticalmethods using them, alone and in conjugation with other drugs,especially diuretics, angiotensin converting enzyme (ACE) inhibitors,and non-steroidal anti-inflammatory drugs (NSAIDS).

The compounds of this invention inhibit the action of the hormoneangiotensin II (All) and am useful therefore in alleviating angiotensininduced hypertension. The enzyme renin acts on a blood plasmaa2-globulin, angiotensinogen, to produce angiotensin I, which is thenconverted by ACE to All. The latter substance is a powerful vasopressoragent which has been implicated as a causative agent for producing highblood pressure in various mammalian species, such as the rat, dog, andman. The compounds of this invention inhibit the action of All at itsreceptors on target cells and thus prevent the increase in bloodpressure produced by this hormone-receptor interaction. By administeringa compound of this invention to a species of mammal with hypertensiondue to All, the blood pressure is reduced. Administration of a compoundof this invention with a diuretic such as furosemide orhydrochlorothiazide, either as a stepwise combined therapy (diureticfirst) or as a physical mixture, enhances the antihypertensive effect ofthe compound. Administration of a compound of this invention with aNSAID can prevent renal failure which sometimes results fromadministration of a NSAID.

Several peptide analogs of All are known to inhibit the effects of thishormone by competitively blocking the receptors, but their experimentaland clinical applications have been limited by their partial agonistactivity and lack of oral absorption (M. Antonaccio, Clin. Exp.Hypertens., 1982, A4, 27-46; D. H. P. Streeten and G. H. Anderson,Jr.--Handbook of Hypertension, Clinical Pharmacology of AntihypertensiveDrugs, ed., A. E. Doyle, Vol. 5, pages 246-271, Elsevier SciencePublisher, Amsterdam, The Netherlands, 1984).

Several non-peptide antagonists of angiotensin II, including somebiphenylmethyl imidazoles, have been disclosed. U.S. Pat. Nos. 5,137,902and 5,138,069 disclose biphenylmethylimidazoles (A) where R¹ may be a##STR2## phenyl substituted in the 2'-position with acidic functionalgroups, such as carboxy and tetrazole, and where imidazole substitutentR⁷ may be alkyl or optionally substituted phenyl, and where R⁸ may beformyl, acyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkoxyalkyl andhydroxyalkyl. U.S. Applications Ser. No. 90/03683 and Ser. No. 07/545302disclose substituted imidazoles of the same basic structure where R⁷ maybe optionally substituted aryl or heteroaryl. European ApplicationEP401,030 (Merck) describes imidazoles of structure (B), where Qrepresents various nitrogenous functional groups, T may be carboxy,alkoxycarbonyl or aminocarbonyl, r may be 1, (X)q can represent a singlebend, R⁶ (B)_(p) may represent alkyl and R¹ may be SO₂ NHR⁹, SO₂NH-heteroaryl, SO₂ NHCOR²⁵ or SO₂ NHCONHR²⁵, where R⁹ is H, alkyl,phenyl or benzyl, and where R²⁵ is aryl, heteroaryl, cycloalkyl oroptionally substituted alkyl.

Australian Application AU-A-80163/91 (EP465,368, Roussel-Uclaf)discloses substituted imidazoles (C) where R¹ may be alkyl, m may be 1,either R² or R³ is OR⁴, or a sulfurous group of structure --S(O)_(n) R⁴,##STR3## --SO(R⁴)═NS(O)_(n) X' or --SSR⁴, where R⁴ represents a varietyof optionally substituted alkyl, alkenyl, alkynyl, acyl or nitrogenousor sulfurous radicals. The imidazole nitrogen substituent (CH₂)_(m) -Ymay represent a biphenylmethyl group, which may be substituted in the2'-position by acidic groups, such as --(CH₂)_(m1) --S(O)_(m2) -X-R¹⁰,in which m1 may be 0-4, m2 may be 0-2, X may be a single bond, --NH--,--NH--CO--, or --NH--CO--NH-- and R¹⁰ is an optionally substitutedalkyl, alkenyl, aryl or heteroaryl radical. European ApplicationEP479,479 (Merck) discloses biphenylmethyl imidazoles (D) where R¹ B mayrepresent alkyl, R³ may be H, alkyl, alkenyl or alkynyl, perfluoroalkyl,halogen, --NO₂, --CN or optionally substituted phenyl, R⁴ includesformyl, acyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkoxyalkyl andhydroxyalkyl, X may be a single bond, and R⁵ includes --SO₂NH-heteroaryl, --SO₂ NHCOR¹² and --SO₂ NHCONR² R¹², in which R² is H oralkyl, and R¹² is aryl, heteroaryl, cycloalkyl, perfluoroalkyl oroptionally substituted C1-C4 alkyl, where the alkyl substituents includearyl, heteroaryl, alkyl, OH, SH, alkoxy, thioalkoxy, halo, carboxy,alkoxycarbonyl, --NO₂, optionally substituted amino and variousphosphoryl radicals. ##STR4##

European patent application number EPA 503, 162, (published Sep. 16,1992, Hoechst Aktiengesellschaft) describes compounds of structure (E)wherein Z can be nitrogen, and X and Y are independently CR². R¹ can bealkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkylalkynyl, or benzyl. R² can be H, halogen, nitroperfluoroalkyl, pentafluorophenyl, cyano, phenyl, phenylalkyl, alkyl,alkenyl, phenylalkenyl, imidazolylalkyl, triazolylalkyl,tetrazolylalkyl, ethers, esters, thioethers, sulfides, sulfoxides,sulfones, amides and other groups as well. L-(O)q-A may represent abiphenylmethyl group which may be substituted in the 2' position with anacidic radical. ##STR5##

None of the above publications disclose the imidazole biphenylsulfonylcarbamates of the present invention. It is well known that two types ofangiotensin II receptors are widely distributed in various mammaliantissues (P. C. Wong et al., Cardiovascular Drug Reviews 1991; 9:.317-339; Trends in Endoctocrinol. Metab. 1992; 3: 211-217). Theangiotensin II receptor most directly involved in the mediation of bloodpressure is termed the AT₁ receptor, and is characterized by highsensitivity to the non-peptide antagonist DuP 753. A second angiotensinII receptor, designated AT₂, is sensitive to another class ofnon-peptide All antagonists, represented by PD 123177 (ibid.), and tothe peptide CGP42112A. Angiotensin II has approximately equal affinityfor both receptor subtypes.

Recent evidence suggests that the AT₂ receptor may have a role inmediating the synthesis and breakdown of cardiac connective tissues. Forexample, Matsubara et ##STR6## al. (The FASEB Journal 6, 4: A941, 1992)have reported that PD123177, but not DuP 753, blocks the All-stimulatedinhibition of collagenase in cultured cardiac fibroblasts. Both PD123177and DuP 753 are reported by Zhou et al. to block the All-stimulatedincrease in collagen synthesis in cardiac fibroblasts (The FASEB Journal6, 4: A1914, 1992).

Tsutsumi and Saavedra have found AT₂ receptors in cerebral arteries (Am.J. Physiol. 261: H667-H670, 1991). An analog of PD123177, PD123319, hasbeen reported by Brix and Haberl (The FASEB Journal 6, 4: A1264, 1992)to block the pial artery dilation induced by angiotensin II in a ratcranial window preparation monitored by intravital microscopy. Thissuggests that the AT₂ receptor may have a role in modifying cerebralblood flow.

The AT₂ selective antagonist CGP42112A has been reported by LeNoble etal. (The FASEB Journal 6, 4: A937, 1992) to block the increase inmicrovascular density induced by angiotensin II in the chickchorioallantoic membrane, suggesting that angiotensin II may in somecontexts mediate angiogenesis through AT₂ receptors.

As noted above, DuP 753, disclosed in U.S. Pat. No. 5,138,069, is aselective AT₁ antagonist, having extremely low affinity for the AT₂receptor. No data is presented in U.S. Pat. No. 5,138,069 or the otherreferences above which suggests that any of the compounds disclosedpossess high AT₂ affinity.

In addition to potent AT₁ antagonist and antihypertensive properties,the imidazole compounds of the present invention possess potent AT₂antagonist properties. Since AT₁ antagonism leads to increased levels ofcirculating angiotensin II in vivo (Y. Christen et al., Am. J.Hypertension, 1991; 4: 350S-353S), and the AT₂ -mediated consequences,if any, of higher All levels are unknown, simultaneous AT₁ /AT₂antagonism may prove desirable during AT₁ -targeted therapy.

SUMMARY OF THE INVENTION

This invention pertains to novel angiotensin II blocking imidazolecompounds of the following Formula (I): ##STR7## wherein R¹ is in themeta or para position and is

(a) 4-CO₂ H,

(b) --CH₂ CO₂ H,

(c) --C(CF₃)₂ OH,

(d) --CONHNHSO₂ CF₃,

(e) 4-CONHCH(CO₂ H)CH₂ C₆ H₅ (L-isomer),

(f) 4-CONHOR¹²,

(g) --CONHSO₂ R¹⁰,

(h) --CONHSO₂ NHR⁹,

(i) --C(OH)R⁹ PO₃ H₂,

(j) --NHCOCF₃,

(k) --NHCONHSO₂ R¹⁰,

(l) --NHPO₃ H₂,

(m) 4-NHSO₂ R¹⁰,

(n) --NHSO₂ NHCOR¹⁰,

(o) --OPO₃ H₂,

(p) --OSO₃ H,

(q) --PO₃ H₂,

(r) --PO(OH)R⁹,

(s) --SO₃ H,

(t) --SO₂ NHR⁹,

(u) --SO₂ NHCOR¹⁰,

(v) --SO₂ NHCONHR⁹, ##STR8##

(ii) --SO₂ NHCO₂ R¹⁰ ;

R² is independently

(a) H,

(b) halo (F, Cl, Br, I),

(c) C₁ -C₄ -alkyl,

(d) C₁ -C₄ -alkoxy,

(e) C₁ -C₄ -acyloxy,

(f) C₁ -C₄ -alkylthio,

(g) C₁ -C₄ -alkylsulfinyl,

(h) C₁ -C₄ -alkylsulfonyl,

(i) --(C₁ -C₄ -alkyl)-OH,

(j) --(C₁ -C₄) alkyl-aryl,

(k) --CO₂ H,

(l) --CN,

(m) tetrazol-5-yl,

(n) --CONHOR₁₂,

(o) --SO₂ NHR⁹,

(p) --NH₂,

(q) C₁ -C₄ -alkylamino,

(r) C₁ --C₄ -dialkylamino,

(s) --NHSO₂ R¹⁰,

(t) --NO₂,

(u) furyl,

(v) phenyl or phenyl optionally substituted with one or two substituentsselected from the group consisting of halo, C₁ -C₄ -alkyl, C₁ -C₄-alkoxy, --NO₂, --CF₃, C₁ -C₄ -alkylthio, --OH, --NH₂, C₁ -C₄-alkylamino, C₁ -C₄ -dialkylamino, --CN, --CO₂ R¹², acetyl;

R³ is independently

(a) H,

(b) halo,

(c) C₁ -C₄ -alkyl,

(d) C₁ -C₄ -alkoxy, or

(e) --C₁ -C₄ -alkyl-(C₁ -C₄ -alkoxy);

R⁴ is

(a) --CN,

(b) --NO₂, or

(c) --CO₂ R¹¹ ;

R⁵ is

(a) H,

(b) C₁ -C₆ -alkyl,

(c) C₃ -C₆ -cycloalkyl,

(d) C₂ -C₄ -alkenyl, or

(e) C₂ -C₄ -alkynyl;

R⁶ is

(a) C₁ -C₁₀ -alkyl,

(b) C₃ -C₁₀ -alkenyl,

(c) C₃ -C₁₀ -alkynyl,

(d) C₃ -C₈ -cycloalkyl,

(e) C₃ -C₈ -cycloalkenyl,

(f) --C₁ -C₃ -alkyl-(C₃ -C₈ -cycloalkyl),

(g) --C₁ -C₃ -alkenyl-(C₅ -C₁₀ -cycloalkyl),

(h) --C₁ -C₃ -alkynyl-(C₅ -C₁₀ -cycloalkyl),

(i) --(CH₂)_(s) S(CH₂)_(m) R⁵, or

(j) benzyl, optionally substituted on the phenyl ring with 1-2substituents selected from the group consisting of halo, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy or --NO₂ ;

R⁷ is

(a) C₁ -C₆ -alkyl,

(b) C₃ -C₆ -cycloalkyl,

(c) aryl, or

(d) benzyl, optionally substituted on the phenyl ring with 1-2substituents selected from the group consisting of halo, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy or --NO₂ ;

R⁸ is

(a) H,

(b) halogen (F,Cl, Br, I),

(c) phenyl, or phenyl optionally substituted with halogen (F, Cl, Br,I), C₁ -C₄ -alkyl, --OH, C₁ -C₄ -alkoxy, --NO₂, --NR₂₆ R²⁷, --NR²⁶COR¹¹, --NR²⁶ CO₂ R⁷, --S(O)_(r) R¹⁰, --SO₂ NR²⁶ R²⁷, --NR²⁶ SO₂ R¹⁰,--CF₃,

(d) C₁ -C₆ -alkyl, optionally substituted with

i) OR²⁵,

ii) S(O)_(r) R¹⁰,

iii) NR²³ R²⁴ ,

iv) NR²⁶ COR¹¹,

v) NR²⁶ CO₂ R⁷,

vi) NR²⁶ CONR²³ R²⁴,

vii) OCONR²³ R²⁴,

viii) OCOR¹¹,

ix) aryl,

(e) C₂ -C₆ -alkenyl,

(f) --C₁ -C₄ -alkyl-aryl,

(h) C₁ -C₄ -alkoxy,

(i) C_(v) F_(2v+1) where v=1 to 3,

(j) --S(O)_(r) R¹⁰,

(k) --S(O)₂ NR²³ R²⁴,

(I) --CONR²³ R²⁴,

(m) --COR⁷, or

(n) --CO₂ R¹² ;

R⁹ is

(a) H,

(b) C₁ -C₅ -alkyl,

(c) aryl,

(d) --(C₁ -C₄ -alkyl)-aryl,

(e) heteroaryl, or

(f) C₃ -C₅ -cycloalkyl;

R¹⁰ is

(a) aryl,

(b) C₃ -C₇ -cycloalkyl,

(c) C₁ -C₄ -perfluoroalkyl,

(d) C₁ -C₄ -alkyl, optionally substituted with a substituent selectedfrom the group consisting of aryl, heteroaryl, --OH, --SH, C₁ C₄ -alkyl,C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, --CF₃, halo, --NO₂, --CO₂ R¹², --NH₂,C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino, --PO₃ H₂, or

(e) heteroaryl;

R¹¹, R^(11a) and R^(11b) are independently

(a) H,

(b) C₁ -C₆ -alkyl,

(c) C₃ -C₆ -cycloalkyl,

(d) aryl,

(e) --(C₁ -C₅ -alkyl)-aryl, or

(f) heteroaryl;

R¹² is

(a) H,

(b) methyl, or

(c) benzyl, optionally substituted on the phenyl ring with 1-2substituents selected from the group consisting of halo, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy or --NO₂ ;

R¹³ is

(a) --CO₂ H,

(b) --CH₂ CO₂ H,

(c) --C(CF₃)₂ OH,

(d) --CONHNHSO₂ CF₃,

(e) --CONHOR¹²,

(f) --CONHSO₂ R¹⁰,

(g) --CONHSO₂ NHR₉,

(h) --C(OH)R₉ PO₃ H₂,

(i) --NHCOCF₃,

(j) --NHCONHSO₂ R¹⁰,

(k) --NHPO₃ H₂,

(l) --NHSO₂ R¹⁰,

(m) --NHSO₂ NHCOR¹⁰,

(n) --OPO₃ H₂,

(o) --OSO₃ H,

(p) --PO(OH)R⁹,

(q) --PO₃ H₂,

(r) --SO₃ H,

(s) --SO₂ NHR⁹,

(t) --SO₂ NHCOR¹⁰,

(u) --SO₂ NHCONHR⁹,

(v) --SO₂ NHCO₂ R¹⁰, ##STR9## R¹⁴ is

(a) H,

(b) C₁ -C₆ -alkyl,

(c) --CH₂ CH═CH₂, or

(d) benzyl, optionally substituted on the phenyl ring with 1-2substituents selected from the group consisting of halo, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy or --NO₂ ;

R¹⁵ is

(a) H,

(b) C₁ -C₈ -alkyl,

(c) C₁ -C₈ -perfluoroalkyl,

(d) C₃ -C₆ -cycloalkyl,

(e) aryl, or

(f) benzyl, optionally substituted on the phenyl ring with 1-2substituents selected from the group consisting of halo, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy or --NO₂ ;

R¹⁶ is

(a) H,

(b) C₁ -C₆ -alkyl, or

(c) benzyl, optionally substituted on the phenyl ring with 1-2substituents selected from the group consisting of halo, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy or --NO₂ ;

R¹⁷ is

(a) H,

(b) C₁ -C₆ -alkyl,

(c) C₃ -C₆ -cycloalkyl,

(d) aryl, or

(e) benzyl, optionally substituted on the phenyl ring with 1-2substituents selected from the group consisting of halo, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy or --NO₂ ;

R¹⁸ is

(a) --NR¹⁹ R²⁰,

(b) --NHCONH₂,

(c) --NHCSNH₂, or

(d) --NHSO₂ -C₆ H₅ ;

R¹⁹ and R²⁰ are independently

(a) H,

(b) C₁ -C₅ -alkyl, or

(c) aryl,

R²¹ and R²² are independently

(a) C₁ -C₄ -alkyl,

or taken together are

(b) --(CH₂)_(q) --;

R²³ and R²⁴ are, independently

(a) H,

(b) C₁ -C₆ -alkyl,

(c) aryl, or

(d) --(C₁ -C₄ -alkyl)-aryl, or

(e) R²³ and R²⁴ when taken together constitute a pyrrolidine, piperidineor morpholine ring;

R²⁵ is

(a) H,

(b) C₁ -C₆ -alkyl,

(c) aryl,

(d) --(C₁ -C₄ -alkyl)-aryl,

(e) C₃ -C₆ -alkenyl, or

(f) --(C₃ -C₆ -alkenyl)-aryl;

R²⁶ and R²⁷ are independently

(a) H,

(b) C₁ -C₄ -alkyl,

(c) aryl, or

(d) --CH₂ -aryl;

R²⁸ is

(a) aryl, or

(b) heteroaryl;

R²⁹ is

(a) --CHO,

(b) --CONH₂,

(c) --NHCHO,

(d) --CO-(C₁ -C₆ perfluomalkyl),

(e) --S(O)_(r) -(C₁ -C₆ perfluoroalkyl),

(f) --O-(C₁ -C₆ perfluoroalkyl), or

(g) --NR^(11a) -(C₁ -C₆ perfluoroalkyl);

R³⁰ is

(a) --CHO,

(b) --SO₂ -(C₁ -C₆ perfluoroalkyl), or

(c) --CO-(C₁ -C₆ perfluoroalkyl);

A is

(a) --(CH₂)_(n) -L¹ -B-(T)_(y) -(B)_(y) -X² -(B)_(y) -R²⁸,

(b) --(CH₂)_(n) -L¹ -B-T-(B)_(y) -R²⁸,

(c) --(CH₂)_(n) -L¹ -B-(T)_(y) -(B)_(y) -X² -B,

(d) --(CH₂)_(n) -L¹ -B-T-(B)_(y) -R²⁹,

(e) --(CH₂)_(n) -L¹ -T-(B)_(y) -X² -(B)_(y) -R²⁸,

(f) --(CH₂)_(n) -L¹ -T-(B)_(y) -R²⁸,

(g) --(CH₂)_(n) -L¹ -T-(B)_(y) -X² -B,

(h) --(CH₂)_(n) -L¹ -(CR¹⁹ R²⁰)-D-(T)_(y) -(B)y-X³ -(B)_(y) -R²⁸,

(i) --(CH₂)_(n) -L¹ -(OR¹⁹ R²⁰)-D-T-(B)_(y) -R²⁸,

(j) --(CH₂)_(n) -L¹ -(CR¹⁹ R²⁰)-D-(T)_(y) -(B)_(y) -X³ -B,

(k) --(CH₂)_(n) -L¹ -(CR¹⁹ R²⁰)-D-T-(B)_(y) -R²⁹,

(l) --(CH₂)_(n) -L¹ -(CR¹⁹ R²⁰)-D-T-(B)_(y) -X⁴ -(B)_(y) -R²⁸,

(m) --(CH₂)_(n) -L¹ -(CR¹⁹ R²⁰)-D-B-X⁴ -(B)_(y) -R²⁸,

(n) --(CH₂)_(n) -L¹ -(CR¹⁹ R²⁰)-D-T-(B)_(y) -X⁴ -B,

(o) --(CH₂)_(n) -L¹ -(CR¹⁹ R²⁰)-D-B-X⁴ -B,

(p) --(CH₂)_(n) -L² -B-(T)_(y) -(B)_(y) -X² -(B)_(y) -R²⁸,

(q) --(CH₂)_(n) -L² -B-T-(B)_(y) -R²⁸,

(r) --(CH₂)_(n) -L² -B-(T)_(y) -(B)_(y) -X₂ -B,

(s) --(CH₂)_(n) -L² -B-T-(B)_(y) -R²⁹,

(t) --(CH₂)_(n) -L² -T-(B)_(y) -X² -(B)_(y) -R²⁸,

(u) --(CH₂)_(n) -L² -T-(B)_(y) -R²⁸,

(v) --(CH₂)_(n) -L² -T-(B)_(y) -X² -B,

(w) --(CH₂)_(n) -L² -D-(T)_(y) -(B)_(y) -X³ -(B)_(y) -R²⁸,

(x) --(CH₂)_(n) -L² -D-T-(B)_(y) -R²⁸,

(y) --(CH₂)_(n) -L² -D-(T)_(y) -(B)_(y) -X³ -B,

(z) --(CH₂)_(n) -L² -D-T-(B)_(y) -R²⁹,

(aa) --(CH₂)_(n) -L² -D-T-(B)_(y) -X⁴ -(B)_(y) -R²⁸,

(bb) --(CH²)_(n) -L² -D-B-X⁴ -(B)_(y) -R²⁸,

(cc) --(CH₂)_(n) -L² -D-T-(B)_(y) -X⁴ -B,

(dd) --(CH₂)_(n) -L² -D-B-X⁴ -B,

(ee) --(CH₂)_(m) -L³ -B-(T)_(y) -(B)_(y) -X² -(B)_(y) -R²⁸,

(ff) --(CH₂)_(m) -L³ -B-T-(B)_(y) -R²⁸,

(gg) --(CH₂)_(m) -L³ -B-(T)_(y) -(B)_(y) -X² -B,

(hh) --(CH₂)_(m) -L³ -B-T-(B)_(y) -R²⁹,

(ii) --(CH₂)_(m) -L³ -T-(B)_(y) -X² -(B)_(y) -R²⁸,

(jj) --(CH₂)_(m) -L³ -T-(B)_(y) -R²⁸,

(kk) --(CH₂)_(m) -L³ -T-(B)_(y) -X² -B,

(ll) --(CH₂)_(m) -L³ -(CR¹⁹ R²⁰)-D-(T)_(y) -(B)_(y) -X³ -(B)_(y) -R²⁸,

(mm) --(CH₂)_(m) -L³ -(CR¹⁹ R²⁰)-D-T-(B)_(y) -R²⁸,

(nn) --(CH₂)_(m) -L³ -(CR¹⁹ R²⁰)-D-(T)_(y) -(B)_(y) -X³ -B,

(oo) --(CH₂)_(m) -L³ -(CR¹⁹ R²⁰)-D-T-(B)_(y) -R²⁹,

(pp) --(CH₂)_(m) -L³ -(CR¹⁹ R²⁰)-D-T-(B)_(y) -X⁴ -(B)_(y) -R²⁸,

(qq) --(CH₂)_(m) -L³ -(CR¹⁹ R²⁰)-D-(B)-X⁴ -(B)_(y) -R²⁸,

(rr) --(CH₂)_(m) -L³ -(CR¹⁹ R²⁰)-D-T-(B)_(y) -X⁴ -B,

(ss) --(CH₂)_(m) -L³ -(CR¹⁹ R²⁰)-D-B-X⁴ -B, ##STR10## L¹ is

(a) --CO₂ --,

(b) --CONR^(11a) --,

(c) --NR^(11a) CO₂ --, or

(d) --NR^(11a) CONR^(11b) --;

L² is

(a) --CO--,

(b) NR^(11a) CO--, or

(c) --O₂ C--;

L3 is

(a) --O--,

(b) --SO--, or

(c) --NR^(11a) --;

B is C₁ -C₆ alkyl;

D is C₂ -C₈ alkenyl or C₂ -C₈ alkynyl;

T is

(a) arylene, , or

(b) heteroarylene

X¹ is

(a) a carbon-carbon single bond,

(b) --CO--,

(c) --C(R¹⁹)(R²⁰)--,

(d) --O--,

(e) --S--,

(f) --SO--,

(g) --SO₂ --,

(h) --NR¹⁴ --,

(i) --CONR₁₆ --,

(j) --NR¹⁶ CO--,

(k) --OC(R¹⁹)(R²⁰)--,

(l) --C(R¹⁹)(R²⁰)O--,

(m) --SC(R¹⁹)(R²⁰)--,

(n) --C(R¹⁹)(R²⁰)S--,

(o) --NHC(R¹⁹)(R²⁰)--,

(p) --C(R¹⁹)(R²⁰)NH--,

(q) --NR¹⁶ SO₂ --,

(r) --SO₂ N R¹⁶ --,

(s) --CH═CH--,

(t) --CF═CF--,

(u) --CF═CH--,

(v) --CH═CF--,

(w) --CF₂ CF₂ --,

(x) --CH(OR¹⁵)--,

(y) --CH(OCOR¹⁷)--,

(z) --C(═NR¹⁸)--,

(aa) --C(OR²¹)(OR²²)--,

(bb) 1,2-cyclopropyl, or

(cc) 1,1-cyclopropyl;

X² is

(a) --CO--,

(b) --O--,

(c) --S(O)_(r) --,

(d) --(C₁ -C₄ -alkylene)--,

(e) --NR^(11a) CONR^(11b) --,

(f) --CONR^(11a) --,

(g) --NR^(11a) CO--,

(h) --SO₂ NR¹⁶ --,

(i) --NR¹⁶ SO₂ --,

(j) --OCONR^(11a) SO₂ --,

(k) --SO₂ NR^(11a) CO--,

(l) --SO₂ NR^(11a) CO--,

(m) --OCONR^(11a) SO₂ --,

(n) --SO₂ NR^(11a) CONR^(11b) --,

(o) --NR^(11a) CONR^(11b) SO₂ --,

(p) --SO₂ NR^(11a) SO₂ --,

(q) --CONR^(11a) SO₂ NR^(11b) --, or

(r) --NR^(11a) SO₂ NR^(11b) CO--;

X³ is

(a) --CO--,

(b) --SO--,

(c) --SO₂ --,

(d) single bond,

(e) --CONR^(11a) --,

(f) --SO₂ NR¹⁶ --,

(g) --CONR^(11a) SO₂ --,

(h) --SO₂ NR^(11a) CO--,

(i) --SO₂ NR^(11a) CO₂ --,

(j) --SO₂ NR^(11a) CONR^(11b) --,

(k) --SO₂ NR^(11a) SO₂ --, or

(l) --CONR^(11a) SO₂ NR^(11b) --;

X⁴ is

(a) --NR^(11a) CONR^(11b-),

(b) --OCONR^(11a) SO₂ --,

(c) --NR¹⁶ SO₂ --,

(d) --OCONR^(11a) SO₂ --,

(e) --NR^(11a) CONR^(11b) SO₂ --, or

(f) --NR^(11a) SO₂ NR^(11b) CO--;

X⁵ is

(a) --CO--,

(b) --SO₂ --,

(c) --COO--, or

(d) --CONR^(11a) --;

Z is

(a) --O--,

(b) --S--, or

(c) --NR¹¹ --;

k is 1 or 2;

m is 1 to 5;

n is 0 to 2;

q is 2 to 3;

r is 0 to 2;

s is 0 to 5;

t is 0 to 3;

u is 2 to 5;

y is 0 or 1;

and pharmaceutically acceptable salts of these compounds.

Preferred compounds of this invention are those of formula (I) wherein

A is

(a) --(CH₂)_(n) -L¹ -S-(T)_(y) -(S)_(y) -X² -(S)_(y) -R²⁸,

(b) --(CH₂)_(n) -L¹ -B-T-(B)_(y) -R²⁸,

(c) --(CH₂)_(n) -L¹ -B-(T)_(y) -(B)_(y) -X² -B,

(d) --(CH₂)_(n) -L¹ -B-T-(B)_(y) -R²⁹

(e) --(CH₂)_(n) -L² -B-(T)_(y) -(B)_(y) -X² -(B)_(y) -R²⁸,

(f) --(CH₂)_(n) -L² -B-T-(B)_(y) -R²⁸, or

(g) --(CH₂)_(n) -L² -B-(T)_(y) -(B)_(y) -X² -B,

(h) --(CH₂)_(n) -L² -B-T-(B)_(y) -R²⁹ ;

One embodiment of the preferred invention above is a compound of formulaII ##STR11## wherein R² is independently

(a) H,

(b) halo (F, Cl, Br, I), or

(c) C₁ -C₄ -alkyl;

R³ is

(a) H, or

(b) halo (F, Cl, Br, I);

R⁶ is

(a) C₁ -C₁₀ alkyl,

(b) C₃ -C₁₀ alkenyl, or

(c) C₃ -C₁₀ alkynyl;

R9 is

(a) H,

(b) C₁ -C₅ -alkyl,

(c) aryl,

(d) --(C₁ -C₄ -alkyl)-aryl, or

(e) heteroaryl;

R¹⁰ is

(a) aryl,

(b) C₃ -C₇ -cycloalkyl,

(c) C₁ -C₄ -perfluoroalkyl,

(d) C₁ -C₄ -alkyl, optionally substituted with a substituent selectedfrom the group consisting of aryl, heteroaryl, --OH, --SH, C₁ -C₄-alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, --CF₃, halo, --NO₂, --CO₂R¹², --NH₂, C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino, --PO₃ H₂, or

(e) heteroaryl;

R¹¹, R^(11a) and R^(11b) are independently

(a) H,

(b) C₁ -C₆ -alkyl,

(c) C₃ -C₆ -cycloalkyl,

(d) aryl,

(e) --(C₁ -C₅ -alkyl)-aryl, or

(f) heteroaryl;

R¹³ is

(a) --CO₂ H,

(b) --CONHSO₂ R¹⁰,

(c) --CONHSO₂ NHR⁹,

(d) --NHCONHSO₂ R¹⁰,

(e) --NHSO₂ R¹⁰,

(f) --NHSO₂ NHCOR¹⁰,

(g) --SO₂ NHR⁹,

(h) --SO₂ NHCOR¹⁰,

(i) --SO₂ NHCONHR⁹,

(j) --SO₂ NHCO₂ R¹⁰, or ##STR12## R¹⁶ is

(a) H,

(b) C₁ -C₆ -alkyl, or

(c) benzyl, optionally substituted on the phenyl ring with 1-2substituents selected from the group consisting of halo, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy or --NO₂ ;

R²⁸ is

(a) aryl, or

(b) heteroaryl;

R²⁹ is

(a) --CHO,

(b) --CONH₂,

(c) --NHCHO,

(d) --CO-(C₁ -C₆ perfluomalkyl),

(e) --S(O)_(r) -(C₁ -C₆ perfluoroalkyl),

E is

(a) --(T)_(y) -(B)_(y) -X₂ -(B)_(y) -R²⁸,

(b) --T-(B)_(y) -R²⁸,

(c) --(T)_(y) -(B)_(y) -X² -B or,

(d) --T-(B)_(y) -R²⁹ ;

L¹ is

(a) --CO₂ --,

(b) --CONR^(11a) --,

(c) --NR^(11a) CO₂ --,

(d) --NR^(11a) CONR^(11b) --;

B is C₁ -C₆ alkyl;

X² is

(a) --CO--,

(b) --O--,

(c) --S(O)_(r) --,

(d) --(C₁ -C₄ -alkylene)-,

(e) --NR^(11al) CONR^(11b) --,

(f) --CONR^(11a) --,

(g) --NR^(11a) CO--,

(h) --SO₂ NR¹⁶ --,

(i) --NR¹⁶ SO₂ --,

(j) --CONR^(11a) SO₂ --,

(k) --SO₂ NR^(11a) CO--,

(l) --SO₂ NR^(11a) CO₂ --,

(m) --OCONR^(11a) SO₂ --,

(n) --SO₂ NR^(11a) CONR^(11b) --,

(o) --NR^(11a) CONR^(11b) SO₂ --,

(p) --SO₂ NR^(11a) SO₂ --,

(q) --CONR_(11a) SO₂ NR^(11b) --, or

(r) --NR^(11a) SO₂ NR^(11b) CO--

and pharmaceutically acceptable salts of these compounds.

Another embodiment of the preferred invention is a compound of FormulaIII ##STR13## wherein R² is independently

(a) H,

(b) halo (F, Cl, Br, I), or

(c) C₁ -C₄ -alkyl;

R³ is

(a) H, or

(b) halo (F, Cl, Br, I);

R⁶ is

(a) C₁ -C₁₀ alkyl,

(b) C₃ -C₁₀ alkenyl, or

(c) C₃ -C₁₀ alkynyl;

R⁹ is

(a) H,

(b) C₁ -C₅ -alkyl,

(c) aryl

(d) --(C₁ -C₄ -alkyl)-aryl, or

(e) heteroaryl;

R¹⁰ is

(a) aryl,

(b) C₃ -C₇ -cycloalkyl,

(c) C₁ -C₄ -perfluoroalkyl,

(d) C₁ -C₄ -alkyl, optionally substituted with a substituent selectedfrom the group consisting of aryl, heteroaryl, --OH, --SH, C₁ -C₄-alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, --CF₃, halo, --NO₂, --CO₂R¹², --NH₂, C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino, --PO₃ H₂, or

(e) heteroaryl;

R¹¹, R^(11a) and R^(11b) are independently

(a) H,

(b) C₁ -C₆ -alkyl,

(c) C₃ -C₆ -cycloalkyl,

(d) aryl,

(e) --(C₁ -C₅ -alkyl)-aryl, or

(f) heteroaryl;

R¹³ is

(a) --CO₂ H,

(b) --CONHSO₂ R¹⁰,

(c) --CONHSO₂ NHR⁹,

(d) --NHCONHSO² R¹⁰,

(e) --NHSO² R¹⁰,

(f) --NHSO₂ NHCOR¹⁰,

(g) --SO₂ NHR⁹,

(h) --SO₂ NHCOR¹⁰,

(i) --SO₂ NHCONHR⁹,

(j) --SO₂ NHCO₂ R¹⁰, or ##STR14## R¹⁶ is

(a) H,

(b) C₁ -C₆ -alkyl, or

(c) benzyl, optionally substituted on the phenyl ring with 1-2substituents selected from the group consisting of halo, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy or --NO₂ ;

R²⁸ is

(a) aryl, or

(b) heteroaryl;

R²⁹ is

(a) --CHO,

(b) --CONH₂,

(c) --NHCHO,

(d) --CO-(C₁ -C₆ perfluomalkyl),

(e) --S(O)_(r) -(C₁ -C₆ perfluoroalkyl),

G is

(a) --(T)_(y) -(B)_(y) -X² -(B)_(y) -R²⁸,

(b) --T-(B)_(y) -R²⁸,

(c) --(T)_(y) -(B)_(y) -X² -B, or

(d) --T-(B)_(y) -R²⁹ ;

L² is --CO--, --NR^(11a) CO-- or --O₂ C--;

B is C₁ -C₆ alkyl;

X² is

(a) --CO--,

(b) --O--,

(c) --S(O)_(r) --,

(d) --(C₁ -C₄ -alkylene)--,

(e) --NR^(11a) CO, --NR^(11a) CONR^(11b) --,

(f) --CONR^(11a) --,

(g) --NR^(11a) CO--,

(h) --SO₂ NR¹⁶ --,

(i) --NR¹⁶ SO₂ --,

(j) --SO₂ NR^(11a) SO₂ --,

(k) --SO₂ NR^(11a) CO₂ --,

(l) --SO₂ NR^(11a) CO₂ --,

(m) --OCONR^(11a) SO₂ --,

(n) --SO₂ NR^(11a) CONR^(11b) --,

(o) --NR^(11a) CONR^(11b) SO₂ --,

(p) --SO₂ NR^(11a) SO₂ --,

(q) --CONR^(11a) SO₂ NR^(11b) --, or

(r) --NR^(11a) SO₂ NR^(11b) CO--

and pharmaceutically acceptable salts of these compounds.

Illustrative of the preferred compounds of the invention are thefollowing:

1-((2'-((i-Amyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-benzoyl-N-phenylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((n-Butyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-benzoyl-N-phenylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((n-Propyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-benzoyl-N-phenylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((n-Butyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-benzoyl-N-butylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((n-Butyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-benzoyl-N-propylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((n-Butyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-butyryl-N-propylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((n-Butyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-butyryl-N-phenylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((i-Amyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-butyryl-N-phenylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((i-Amyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-isonicotinoyl-N-pyridin-3-ylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((n-Butyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-isonicotinoyl-N-pyridin-3-ylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((n-Butyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-nicotinoyl-N-pyridin-3-ylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((i-Amyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-nicotinoyl-N-pyridin-3-ylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((i-Amyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-nicotinoyl-N-pyridin-2-ylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((i-Amyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-isonicotinoyl-N-phenylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((i-Amyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-butyryl-N-pyridin-3-ylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((i-Amyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-isobutyryl-N-pyridin-3-ylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((n-Butyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-acetyl-N-pyridin-3-ylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((i-Amyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-butyryl-N-pyridin-2-ylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((i-Amyloxycarbonylamino)sulfonyl)-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-butyryl-N-pyridin-3-ylamino)ethylcarbonyl]-2-butyl-4-chloro-1H-imidazole

1-((2'-((i-amyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-propionyl-N-pyridin-3-ylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((i-Amyloxycarbonylamino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-nicotinoyl-N-pyridin-3-ylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((i-Amyloxycarbonylamino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-5-[2(N-butyryl-N-pyridin-3-ylamino)ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole

1-((2'-((n-Butyloxycarbonyl-amino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-4-ethyl-5-(2-(2-phenoxyphenyl)ethylcarbonyl)-2-propyl-1H-imidazole

4-[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-n-butyloxycarbonylaminosulfonyl-1,1'-biphenyl

4-[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-((2-phenyl)ethyloxycarbonylaminosulfonyl)-1,1'-biphenyl

4-[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-2'-((2-phenyl)ethyloxycarbonylaminosulfonyl)-1,1'-biphenyl

4-[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-n-butyloxycarbonylaminosulfonyl-1,1'-biphenyl

4-[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-n-isoamyloxycarbonylaminosulfonyl-1,1'-biphenyl

4-[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-2'-n-isoamyloxycarbonylaminosulfonyl-1,1'-biphenyl

4-[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-n-propyloxycarbonylaminosulfonyl-1,1'-biphenyl

4-[((5-(2-Isoamyloxybenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-n-butyloxycarbonylaminosulfonyl-1,1'-biphenyl

4-[((5-(2-Phenylaminocarbonyl)benzyloxycarbonyl-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-n-butyloxycarbonylaminosulfonyl-1,1'-biphenyl.

4-[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-(1H-tetrazol-5-yl)-1,1'-biphenyl

4-[((5-)2-trifluorophenyl)methylaminocarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-isoamyloxycarbonylaminosulfonyl-1,1'-biphenyl

N-butyl, N-benzyl-2-(aminocarbonyl)ethynylmethyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate

N, N-diphenyl-2-(aminocarbonyl)ethynylmethyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate

N-phenyl-2-(aminocarbonyl)ethyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate

N-butyl, N-benzyl-4-(aminocarbonyl)propyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate

N, N-dipentyl-4-(aminocarbonyl)propyl4-ethyl-2-propyl-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate

4-[(5-((2-benzoyl)phenylcarbonyloxymethyl)-4-chloro-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-isoamyloxycarbonylaminosulfonylbiphenyl

1-((2'-((n-butyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazole

Note that throughout the text when an alkyl substituent is mentioned,the normal alkyl structure is meant (e.g. butyl is n-butyl) unlessotherwise specified. However, in the definition of radicals above (e.g.R³), both branched and straight chains are included in the scope ofalkyl, alkenyl and alkynyl.

The term aryl is meant to include phenyl, biphenyl, napthyl, orfluorenyl group optionally substituted with one to three substituentsselected from the group consisting of --OH, --SH, C₁ -C₄ -alkyl, C₁ -C₄-alkoxy, --CF₃, halo, --NO₂, --CO₂ H, --CO₂ CH₃, --CO₂ -benzyl, --NH₂,--NH(C₁ -C₄ -alkyl), --N(C₁ -C₄ -alkyl)₂. The term heteroaryl is meantto include unsubstituted, monosubstituted or disubstituted 5- to10-membered mono- or bicyclic aromatic rings which can optionallycontain from 1 to 3 heteroatoms selected from the group consisting of O,N, and S. Included in the definition of the group heteroaryl, but notlimited to, are the following: pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazinyl, furyl, thiophenyl, imidazolyl, oxazolyl,thiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, indolin-2-onyl, indolinyl, indolyl, pyrrolyl,quinonlinyl and isoquinolinyl. Particularly preferred are 2-, 3-, or4-pyridyl; 2-, or 3-furyl; 2-, or 3-thiophenyl; 2-, 3-, or 4-quinolinyl;or 1-, 3-, or 4-isoquinolinyl optionally substituted with one to threesubstituents selected from the group consisting of --OH, --SH, C₁ -C₄-alkyl, C₁ -C₄ -alkoxy, --CF₃, halo, --NO₂, --CO₂ H, --CO₂ CH₃, --CO₂-benzyl, --NH₂, --NH(C₁ -C₄ -alkyl), --N(C₁ -C₄ -alkyl)₂. The termarylene is meant to include a phenyl, biphenyl, napthyl, or fluorenylgroup which is used as a link for two groups to form a chain. Includedin the definition of arylene, but not limited to, are the followingisomeric linkers: 1,2-phenyl, 1,3-phenyl, 1,4-phenyl; 4,4'-biphenyl,4,3'-biphenyl, 4,2'-biphenyl, 2,4'-biphenyl, 2,3'-biphenyl,2,2'-biphenyl, 3,4'-biphenyl, 3,3'-biphenyl, 3,2'-biphenyl,;1,2-napthyl, 1,3-napthyl, 1,4-napthyl, 1,5-napthyl, 1,6-napthyl,1,7-napthyl, 1,8-napthyl, 2,6-napthyl, 2,3-napthyl; 1,4-fluorenyl.Particularly preferred are 1,2-phenyl, 1,3-phenyl, 1,4-phenyl,4,4'-biphenyl, 3,3'-biphenyl, and 2,2'-biphenyl optionally substitutedwith one to three substituents selected from the group consisting of--OH, --SH, C₁ -C₄ alkyl, C₁ -C₄ -alkoxy, --CF₃, halo, --NO₂, --CO₂ H,--CO₂ CH₃, --CO₂ -benzyl, --NH₂, --NH(C₁ -C₄ -alkyl), --N(C₁ -C₄-alkyl)₂.

The term heteroarylene is meant to include unsubstituted 5- to10-membered aromatic ring which can optionally contain from 1 to 3heteroatoms selected from the group consisting of O, N, and S which isused as a link for two groups to form a chain. Included in thedefinition of the group heteroaryl, but not limited to, are thefollowing: 2,3-pyridyl, 2,4-pyridyl, 2,5-pyridyl, 2,6-pyridyl,3,4-pyridyl, 3,5-pyridyl, 3,6-pyridyl; 2,3-furyl, 2,4-furyl, 2,5-furyl;2,3-thiophenyl, 2,4-thiophenyl, 2,5-thiophenyl; 4,5-imidazolyl,4,5-oxazolyl; 4,5-thiazolyl; 2,3-benzofuranyl; 2,3-benzothiophenyl;2,3-benzimidazolyl; 2,3-benzoxazolyl; 2,3-benzothiazolyl;3,4-indolin-2-onyl; 2,4-indolinyl; 2,4-indolyl; 2,4-pyrrolyl;2,4-quinolinyl, 2,5-quinolinyl, 4,6-quinolinyl; 3,4-isoquinolinyl,1,5-isoquinolinyl. Particularly preferred are 2,3-pyridyl, 3,4-pyridyl,2,3-furyl, 3,4-furyl 2,3-thiophenyl, 3,4-thiophenyl, 2,3-quinolinyl,3,4-quinolinyl and 1,4-isoquinolinyl optionally substituted with one tothree substituents selected from the group consisting of --OH, --SH, C₁-C₄ -alkyl, C₁ -C₄ -alkoxy, --CF₃, halo, --NO₂, --CO₂ H, --CO₂ CH₃,---CO₂ -benzyl, --NH₂, --NH(C₁ -C₄ -alkyl), --N (C₁ -C₄ -alkyl)₂ ;

Pharmaceutically acceptable salts include both the metallic (inorganic)salts and organic salts; a non-exhaustive list of which is given inRemington's Pharmaceutical Sciences 17th Edition, pg. 1418 (1985). It iswell known to one skilled in the art that an appropriate salt form ischosen based on physical and chemical stability, flowability,hydroscopicity and solubility. Preferred salts of this invention for thereasons cited above include potassium, sodium, calcium and ammoniumsalts.

Also within the scope of this invention are pharmaceutical compositionscomprising a suitable pharmaceutical carrier and a novel compound ofFormula (I), (II) or (III), and methods of using the novel compounds ofFormula (I), (II) or (III), to treat hypertension and congestive heartfailure. The pharmaceutical compositions can optionally contain one ormore other therapeutic agents, such as a diuretic, an angiotensin Iconverting enzyme (ACE) inhibitor or a non-steroidal antiinflammatorydrug (NSAID). Also within the scope of this invention is a method ofpreventing renal failure resulting from administration of a NSAID whichcomprises administering a novel compound of Formula (I) in stepwise orphysical combination with the NSAID. The compounds of this invention canalso be used as diagnostic agents to test the renin angiotensin system.

It should be noted in the foregoing structural formula, when a radicalcan be a substituent in more than one previously defined radical, thatfirst radical (R^(#), B or y) can be selected independently in eachpreviously defined radical. For example, R¹ and R² can each be--CONHOR¹². R¹² need not be the same substituent in each of R¹ and R²,but can be selected independently for each of them. Or if, for example,the same R group (let us take R², for instance) appears twice in amolecule, each of those R groups is independent of each other (one R²group may be --CONHOR¹², while the other R² group may be --CN).

It is understood that many of the compounds of the present inventioncontain one or more chiral centers and that these stereoisomers maypossess distinct physical and biological properties. The presentinvention comprises all of the stereoisomers or mixtures thereof. If thepure enantiomers or diastereomers are desired, they may be preparedusing starting materials with the appropriate stereochemistry, or may beseparated from mixtures of undesired stereoisomers by standardtechniques, including chiral chromatography and recrystallization ofdiastereomeric salts.

DETAILED DESCRIPTION OF THE INVENTION

Synthesis

The novel compounds of Formula (I), (II) or (III) may be prepared usingthe reactions and techniques described in this section. The reactions amperformed in a solvent appropriate to the reagents and materialsemployed and suitable for the transformation being effected. It isunderstood by those skilled in the art of organic synthesis that thefunctionality present on the imidazole and other portions of themolecule must be consistent with the chemical transformations proposed.This will frequently necessitate judgement as to the order of syntheticsteps, protecting groups required, and deprotection conditions.Throughout the following section, not all compounds of Formula (I), (II)or (III) falling into a given class may necessarily be prepared by allmethods described for that class. Substituents on the starting materialsmay be incompatible with some of the reaction conditions required insome of the methods described. Such restrictions to the substituentswhich are compatible with the reaction conditions will be readilyapparent to one skilled in the art and alternative methods describedmust then be used.

The imidazole precursors in this application may be prepared asdescribed in U.S. Pat. Nos. 5,137,902 and 5,138,069, in PCT U.S.Application 90/03683 and in European Application EP465,368 (see alsoAustralian Patent AU-A-80163/91) and in U.S. Application (07/544557),which are hereby incorporated by reference.

When L¹ is --CO₂ -- and A is --(CH₂)_(n) -L¹ -B-(T)_(y) -(B)_(y) -X²-(B)_(y) -R²⁸ (subheading (a) of A in the scope of this application)then A may be synthesized by simply alkylating the corresponding freecarboxylic acid A ═--(CH₂)_(n) --COOH of structure (2) with X-B-(T)_(y)-(B)_(y) -X² -(B)_(y) -R²⁸, where X is the corresponding chloride,bromide, tosylate or mesylate in an inert solvent in the presence of anacid scavenger such as potassium carbonate or triethylamine at roomtemperature to the reflux temperature of the solvent. Common inertsolvents include THF, DMF, DMSO, etc. If B is longer than a methylene(CH₂), then to facilitate alkylation, it might be necessary to add somesodium iodide. An example of this alkylation is shown below when for A,subheading (a) and going from left to right, B═CH₂, T=Ph, y=1, y=0, X²=(C═O), y=0 and R²⁸ ═Ph: ##STR15## Or in general, the synthesis may besummarized as in Scheme 1: ##STR16##

The entire side chain need not be fully elaborated in order to performthis alkylation. For example, instead of alkylating with X-B-(T)_(y)-(B)_(y) -X² -(B)_(y) -R²⁸, one may alkylate with X-B-(T)_(y) -(B)_(y)-X^(2'). X^(2') in this case must be a group which can be easilytransformed into X² -(B)_(y) -R²⁸ via condensation reactions. Thereforethis synthetic route applies only where X² is a group such as one of thefollowing: amides (--CONR^(11a) --, --NR^(11a) CO--), ureas (--NR^(11a)CONR^(11b) --), sulfonamides (--SO₂ NR¹⁶ --, --NR¹⁶ SO₂ --),acysulfonamides (--SO₂ NR^(11a) CO--, --CONR^(11a) SO₂ --),sulfonylcarbamates (--OCONR^(11a) SO₂ --), sulfonylureas (--SO₂ NR^(11a)CONR^(11b) --, --NR^(11a) CONR^(11b) SO₂ -), sulfonylsulfonamides (--SO₂NR^(11a) SO₂ --), and aminoacylsulfonamides (--CONR^(11a) SO₂ NR^(11b)--, --NR^(11a) SO₂ NR^(11b) CO--). All of the above groups or linkagesmay be formed via condensation reactions, which am exemplified ineuropean patent application EPA 400 835, published Dec. 5, 1990. Forexample, if one were to synthesize X² ═--CONR^(11a) --, then one mayalkylate the imidazole-5-carboxyl group with X-B-(T)_(y) -(B)_(y)-COO-CH₂ Ph. Subsequent hydrogenation over palladium on carbon in analcohol solvent yields the free carboxylic acid A═--(CH₂)_(n)-COO-B-(T)_(y) -(B)_(y) -COOH. Coupling with amine NHR^(11a) -(B)_(y)-R²⁸ using, for example, N,N'-diclohexylcarbodiimide in DMF or THF assolvent yields A═--(CH₂)_(n) -COO-B-(T)_(y) -(B)_(y) -CONR^(11a)-(B)_(y) -R²⁸. Similar types of synthetic schemes can be applied to theother X² group containing side-chains mentioned in this paragraph.

Amides wherein L¹ ═--CONR^(11a), may be synthesized by the proceduresshown in Scheme 2. Amine (5) is coupled to carboxylic acid (2) using adiimide coupling reagent such as N,N'-dicyclohexylcarbodiimide, etc., inan inert solvent such as DMF to yield amide (6). Another procedureinvolves converting carboxylic acid (2) into an acid chloride with forexample thionyl chloride or oxallyl chloride, procedures familiar to oneskilled in the art. This acid chloride is then coupled with amine (5) bysimply mixing the two together in an inert solvent, such ##STR17## asmethylene chloride over an acid scavenger such as potassium carbonate at0° C. to room temperature to yield amide (6). Alternatively, The entireside chain need not be fully elaborated in order to perform thiscoupling. For example, instead of coupling with HR^(11a) N-B-(T)_(y)-(B)_(y) -X² -(B)_(y) -R²⁸, one may couple with HR^(11a) N-B-(T)_(y)-(B)_(y) -X^(2'). Thus coupling of carboxylic acid (2) with amine (7)under the above described coupling conditions yields amide (8) which canbe subsequently elaborated into amide (6). This of course can only bedone if the X² linker is one which can be formed by condensationreactions, as was described in the section under L¹ ═--COO--. Carbamateswherein L¹ ═--NR^(11a) CO₂ -- may be synthesized by the procedures shownin Scheme 3. Here amine (9) is reacted with chloroformate (10) either inthe presence of aqueous base (Schotten-Baumann reaction: E. Baumann,Ber. Deut. Chem. Ges. 1886, 19, 3218.) or in the presence of an acidscavenger (either 1 equivalent or excess) such as pyridine,triethylamine, or ##STR18## potassium carbonate to yield carbamate (11).If the reaction is sluggish, the chlorofomate might have to be activatedwith 4-N,N-dimethylaminopyridine, either catalytic or excess. Thereaction is done in an inert solvent such as methylene chloride or THF,etc. at 0° C. or room temperature or higher. Likewise as seen earlier,the side-chain may be constructed in two steps, namely reaction of amine(9) with chloroformate (12) to yield carbamate (13) followed byelaboration to carbamate (11 ). This of course can only be done if theX² linker is one which can be formed by condensation reactions, as wasdescribed in the section under L¹ ═--COO--.

Another synthesis of carbamates L¹ ═--NR^(11a) CO₂, involves firstreacting amine (9) (R^(11a) ═H) (synthesis described in U.S. Pat. No.5,138,069) with carbonyldiimidazole in an inert solvent such as THF orDMF at room temperature or with some heating to yield an isocyanate (14)as shown in Scheme 4. Further reaction with an alcohol (15) in an inertsolvent with or without heat yields carbamate (11). Of course, as inScheme 3, the synthesis of the side-chain can also be performed stepwiseif X² can be formed via condensation reactions as was discussed earlier.##STR19## When n=0 in Schemes 3 and 4, then there is a carbamate groupconnected directly to the imidazole 5-position of (9) or (9a). Thecorresponding isocyanate starting material may be made by Curtiusrearrangement (T. L. Capson, C. D. Poulter Tet. Lett. 1982, 25, 3515) ofthe corresponding acyl azide as shown in Scheme 5. Thus, carboxylic acid(17) (prepared as in U.S. Pat. No. 4,760,083) can be converted to itsacid chloride by procedures familiar to one skilled in the art.Subsequent reaction with sodium azide yields acyl azide (19) which isheated to undergo Curtius rearrangement with nitrogen expulsion to yieldisocyanate (14a). Heating acyl azide (19) in the presence of alcohol(15) will yield carbamate (11 ) directly (T. L. Capson, ibid. ). If thealcohol is 2-trimethylsilylethanol, then the resulting carbamate (20)may be decomposed with fluoride ion (T. L. Capson, ibid.) to the amine(21) which can be used to make other carbamate side-chains (or ureas andamides, as seen subsequently). Amine (21) may undergo inductiveamination by procedures familiar to one skilled in the art to yieldalkylated amine (21a). The Curtius rearrangement may be performed in"one pot" by heating carboxylic acid (17) with diphenylphosphorylazideto yield isocyanate (14a) which again can be reacted in the same potwith an alcohol to yield a carbamate (T. Shiori, K. Ninomiya, S. YamadaJ. Am. Chem. Soc. 1972, 94, 6203.

Yet another synthesis of amine (21) is shown below. Here anunsubstituted imidazole at the 5-position is nitrated with HNO₃ and H₂SO₄ under standard conditions. Then the nitro group is reduced withhydrogen over palladium on carbon in an alcohol solvent also understandard conditions to yield (21). ##STR20##

Taking amines (9), (9a), (21), or (21a) and reacting with carbamoylchloride (22) (formed from phosgene and an amine: H. Hopif, H. OhlingerAngew. Chem. 1949, 61, 183) will yield urea (23) (Scheme 6). Likewise,primary amines (9) and (21) may be converted to the correspondingisocyanate as seen earlier and then reacted with an amine to yield urea(23). For example, reaction of isocyanate (14) with an amine such as (5)will yield urea (23). Conversely, amines (9), (9a), (21), or (21a) canbe reacted with isocyanate (24) to yield urea (23). Of course, as inScheme 3, the synthesis of the side-chains discussed in this paragraphcan also be performed stepwise if X² can be formed via condensationreactions as was discussed earlier. ##STR21## The synthesis of--(CH₂)_(n) -L¹ -B-(T)_(y) -(B)_(y) -X² -(B)_(y) -R²⁸ where X² is eithera ketone, ether or thioether am summarized in Scheme 7. Aldehyde (25)may be reacted with Grignard reagent (26) in an inert solvent such asether or THF at 0° C. to room temperature or with some heating to yieldalcohol (27). Oxidation by a variety of methods familiar to one skilledin the art yields ketone (28). These methods include the use of PCC(pyridinium chlorochromate: E. J. Corey, J. W. Suggs Tet. Lett., 1975,47), pyridinium dichromate in methylene chloride (E. J. Corey, G.Schmidt Tet. Lett., 1979, 399), the Swern oxidation using DMSO andtrifluoroacetic anhydride (K. Omura, A. K. Sharma, D. Swern, J. Org.Chem., 1976, 41, 957), the Dess-Martin Periodinane oxidation (D. B.Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4156 and J. P. Burkhart, N.P. Peet, P. Bey, Tet. Lett. 1988, 29, 3433) or a Bobbitt oxidation using4-acetylamino-2,2,6,6-tetramethylpiperidinyl-1-oxyl and toluenesulfonicacid (Z. Ma, J. M. Bobbitt, J. Org. Chem., 1991, 56, 6110). Metalalkoxide (29) is reacted with bromide (30) to undergo S_(N) 2displacement in an inert solvent such as DMF, DMSO, or THF, with orwithout the presence of an iodide salt, to yield ether (31). Likewise,the bromide and alkoxide moieties may be interchanged so that bromide(32) is reacted with alkoxide (33) to yield ether (31) under the sameconditions. The oxygen atom may be replaced with sulfur to yieldthioether products. Once the side-chain is synthesized, the THP group isremoved using aqueous acid and the alcohol can be converted to thebromide via standard methods (PBr₃, CBr₄ & Ph₃ P, etc.) or made into aleaving group such as a tosylate, mesylate or triflate by proceduresfamiliar to one skilled in the art. These can be reacted further withsodium azide in DMSO to form the azide (J. M. Muchowski, Can. J. Chem.1971, 49, 2023) which can be hydrogenated to the amine using hydrogenover palladium on carbon. Or the bromide, tosylate, mesylate or triflatemay be reacted with ammonia to yield the amine directly. ##STR22##

If any y is zero in (CH₂)_(y) of (31), then they are aryl-ethersor-thioethers. These are synthesized employing variations of the Ullmannaryl ether synthesis (A. A. Moroz, M. S. Shvartssberg Russ. Chem. Rev.,1974, 43, 679).

Side-chains represented in the scope by A subheading (b) (--(CH₂)_(n)-L¹ -B-T-(B)_(y) -R₂₈ ) may be synthesized by the methods described in Asubheading (a). When y equals zero, then we have a biaryl, aheteroaryl-aryl, an aryl-heteroaryl, and biheteroaryl system. Thesecompounds may be synthesized by employing aromatic cross-couplingreactions familiar to one skilled in the art. For example, there is theStille Coupling (A. M. Echavarren, J. K. Stille, J. Am. Chem. Soc. 1987,109, 5478; T. R. Bailey, Tet. Lett. 1986, 4407); Suzuki Coupling (N.Miyaura, T. Yanagi, A. Suzuki Syn. Comm. 1981, 11, 513; J.-m. Fu, V.Snieckus Tet. Lett. 1990, 31, 1665); Negishi Coupling (E. Negishi, A. O.King, N. Okukado J. Org. Chem. 1977, 42, 1821; A. S. Bell, D. A.Roberts, K. S. Ruddock, Tet. Lett. 1988, 29, 5013); Ullmann Coupling (W.J. Thompson, J. Gaudino J. Org. Chem. 1984, 49, 5237); and otherreactions and references summarized in a review (V. N. Kalinin Synthesis1992, 413). When y equals one, one can make the biaryl, heteroaryl-aryl,aryl-heteroaryl, and biheteroaryl methylene compounds (B═CH₂) via theNegishi coupling (ibid.). One can also make them from the correspondingketones (C═O) by simply reducing the ketone to the methylene viahydrogenation over palladium on carbon. For y>1, one may employ theWittig reaction (familiar to one skilled in the art) to make thecorresponding biaryl substituted alkenes which can be reduced(hydrogenated over Pd on carbon) to the corresponding alkyl.

Side-chains represented in the scope by A subheading (c) may besynthesized by the methods described in A subheading (a). Side-chainsrepresented in the scope by A subheading (d) may be synthesized by themethods described in A subheading (a) with the appropriate substitutionon T to permit elaboration to R²⁹ (Scheme 8). For example, if T issubstituted with a protected alcohol such as CH₂ (CH₂)_(n) OTHP, wheren=0-6, then the alcohol can be deprotected with aqueous acid or HCl inMeOH to yield the free alcohol. Subsequent oxidation, as with MnO₂ (if n=0), PCC (pyridinium chlorochromate: E. J. Corey, J. W. Suggs Tet.Lett., 1975, 2647), pyridinium dichromate in methylene chloride (E. J.Corey, G. Schmidt Tet. Lett., 1979, 399), Swern oxidation using DMSO andtrifluoroacetic anhydride (K. Omura, A. K. Sharma, D. Swern, J. Org.Chem., 1976, 41, 957), Dess-Martin Periodinate oxidation (D. B. Dess, J.C. Martin, J. Org. Chem. 1983, 48, 4156 and J. P. Burkhart, N. P. Peet,P. Bey, Tet. Lett. 1988, 29, 3433) or a Bobbitt oxidation using4-acetylamino-2,2,6,6-tetramethylpiporidinyl-1-oxyl and toluenesulfonicacid (Z. Ma, J. M. Bobbitt, J. Org. Chem., 1991, 56, 6110) affordsaldehyde (35). An amine can be protected, for example with3,4-dimethoxybenzyl groups. Thus a carboxylic acid can be converted intoits corresponding bis(3,4-dimethoxybenzyl)amine amide by couplingmethods familiar to one skilled in the art. Subsequent hydrogenation oracid cleavage yields amide (36) (M. I. Jones, C. Froussios, D. A. EvansJ. Chem. Soc. Chem. Comm., 1976, 472,). A nitro group is a latent aminofunctionality. Thus R^(29') =NO₂ can be reduced by a variety of methodsfamiliar to one skilled in the art, the easiest of which is simplehydrogenation over a noble metal catalyst to yield an amine. Subsequentrefluxing with ethyl formate in an inert solvent yields formamide (37).R^(29') =S-C_(v) F_(2v+1) may be oxidized by one equivalent of hydrogenperoxide to yield sulfoxide (38) (r=1) or with excess peroxide to yieldsulfone (38) (r=2) (R. L. Shriner, H. C. Struck, W. J. Jorison J. Am.Chem. Soc., 1930, 52, 2066; O. Hinsberg Chem. Ber. 1910, 43, 289).R^(29') =S-C_(v) F2v+1 may be synthesized via S_(N) 2 displacementchemistry by a sulfur nucleophile with an activated leaving group on theperfluoroalkyl group (L. M. Yagupolskii, et al. Synthesis 1978, 835). Avariation of the preceding is an electochemical S_(N) 2 displacement toyield S-perfluoroalkyl compounds (J. Pinson, J.-M. Saveant J. Am. Chem.Soc. 1991, 113, 6872). Another synthesis would be via reduction of thecorresponding perfluoroalkylsulfone, with, for example,diisobutylaluminum hydride (Gardner, et al. Can. J. Chem. 1973, 51,1419). Alkylsulfones are readily available from S_(N) 2 displacementchemistry by sulfinic acid salts (Meek and Fowler J. Org. Chem. 1968,33, 3422), in this case perfluoroalkylsulfinic acid salts. If thesulfide is directly attached to T, then a Friedel-Crafts reaction can beused to directly attach the perfluoroalkylsulfur group to T using C_(v)F_(2v+1) -S-Cl in the presence of SnCl₄ (A. Hass, V. Hellwig Chem. Ber.1976, 109, 2475). This product in turn can be oxidized to thecorresponding sulfoxides and sulfones, selectively. Perfluoroamide (39)may be made from the corresponding deprotected carboxylic acid as shownby diimide coupling methods familiar to one skilled in the art. R²⁹═--CO-C_(v) F_(2v+1) and O----C_(v) F_(2v+1) must be assembled beforeL¹, the linkage to the imidazole, is formed. For the other R²⁹ groups,one has the option of preassembling the side-chain before L¹ is formedor after it is formed. The R²⁹ ═--CO-C_(v) F_(2v+1) and --O--C_(v)F_(2v+1) groups can be prepared easily from commercially availablestarting materials, the procedures of which are familiar to one skilledin the art. For example, a perfluoroalkanoyl-arene or -heteroarene mayundergo Friedel-Crafts alkylation with Cl(CH₂)_(n) Cl to yieldCl-(CH₂)_(n) -T-(B)_(y) -COC_(v) F_(2v+1). This in turn may beelaborated by any of a number of methods previously shown to yieldimidazole (34) where R^(29') =R²⁹ ═--CO--C_(v) F_(2v+1). The same istrue for elaborating perfluoroalkyloxy-arene or -heteroarene to R^(29')═R²⁹ ═--O--C_(v) F_(2v+1).

Grignard reagents will react with anhydrides of perfluoroalkanoic acidsto yield perfluoroalkylketones (United Kingdom Patent, number 2,210,881,issued to Imperial Chemical Industries). Friedel-Crafts acylation ofperfluoalkanoyl species directly onto T will also yieldperfluoroalkanoyl ketones attached directly to T (T. R. Forbus, Jr. J.Org. Chem. 1979, 44, 313; J. W. Harbuck, H. Rapaport J. Org. Chem,,1972, 37, 3618). Perfluoroalkoxyhalides will add across alkenes to yieldperfluoroalkyl haloalkyl ethers (O. Lerman, et al. J. Org. Chem. 1980,45, 4122; D. H. R. Barton, et al. J. Chem. Soc. P. I, 1977, 2604; L. R.Anderson J. Org. Chem. 1970, 35, 3730). Subsequent removal of thechlorine with tribuyltin hydride with a radical initiator will yield theperfluoroalkyl ether, familiar to one skilled in the art. If fluorine(or chlorine, for that matter) was used in the perfluoroalkoxyhalide,then subsequent dehydrofluorination with base followed by hydrogenationover a noble metal catalyst will yield the perfluoroalkyl alkyl ether,by procedures familiar to one skilled in the art. The perfluoroalkoxygroup may be directly attached to T via the Ullmann ether synthesis(Moroz and Schvartsberg Russ. Chem. Rev. 1974, 43, 679). ##STR23##

When A is --(CH₂)_(n) -L¹ -(T)-(B)_(y) -X² -(B)_(y) -R²⁸ (subheading (e)of A in the scope of this application) then A may be synthesized bysimply taking carboxylic acid (2) and coupling it with HO-(T)-(B)_(y)-X² -(B)_(y) -R²⁸ to yield L¹ ═--CO₂ --. This coupling is carried outvia diimide coupling methods familiar to one skilled in the art(N,N-dicyclohexylcarbodiimide). Another way is via conversion of thecarboxylic acid group of (2) to an acid chloride which can be reactedwith the metal alkoxide of HO-(T)-(B)_(y) -X² -(B)_(y) -R²⁸ formed fromreaction with Nail or KH in DMF or another inert solvent, or with thefree alcohol HO-(T)-(B)_(y) -X² -(B)_(y) -R²⁸ using Schotten-Baumannconditions discussed previously. Likewise, the same procedures can beused with HNR^(11a) -(T)-(B)_(y) -X² -(B)_(y) -R²⁸ to yield L¹=-CONR^(11a) --. Procedures in Schemes 3-6 can be used to synthesizeA═--(CH₂)_(n) NR^(11a) CO₂ -(T)-(B)_(y) -X² -(B)_(y) -R²⁸ and--(CH₂)_(n) -NR^(11a) CONR^(11b) -(T)-(B)_(y) X² -(B)_(y) -R²⁸. Ofcourse, as in Scheme 3, the synthesis of the side-chain can also beperformed stepwise if X² can be formed via condensation reactions as wasdiscussed earlier. If X² cannot be formed by condensation reactions aswhen it is a ketone, ether, or thioether, then the syntheses of theseside-chains follows basically the pathway described in Scheme 7. This istrue for all of the X² containing side-chains described in the scope andlisted under A.

Removal of X² from A subheading (e), the side-chain which was previouslydiscussed above, leads to the side-chain described under A subheading(f) , or namely --(CH₂)_(n) -L¹ -(T)-(B)_(y) -R²⁸. This side-chain maybe synthesized by the procedures described for A when A is --(CH₂)_(n)-L¹ -(T)-(B)_(y) -X² -(B)_(y) -R²⁸ (subheading (e)). When y=0, then anyof the aryl cross-coupling reactions described previously may be used tosynthesize the carbon-carbon bond between T and R²⁸. When y=1, then theNegishi coupling reaction may be used to synthesize the T-CH₂ -R²⁸ unit.One can also make them from the corresponding ketones by simply reducingthe ketone to the methylene via hydrogenation over palladium on carbon.For y>1, one may employ the Wittig reaction (familiar to one skilled inthe art) to make the corresponding biaryl, or biheteroaryl oraryl-heteroaryl substituted alkenes which can be reduced to thecorresponding alkyl to yield the T--(CH₂)_(n) -R²⁸ unit.

Removal of R²⁸ from the side-chain described in A, subheading (e), leadsto the side-chain described under A subheading (g), or namely--(CH₂)_(n) -L¹ -(T)-(B)_(y) -X² -B. Here the synthesis is basically thesame as described in A subheading (e).

A is --(CH₂)_(n) -L¹ -(CR¹⁹ R²⁰)-D-(T)_(y) -(B)_(y) -X³⁻⁻ (B)_(y) -R²⁸(subheading (h)) can be synthesized by the methods described in Schemes9 and 10. ##STR24##

Scheme 9 describes the synthesis of D=alkenyl where the double bond isdirectly connected to CR¹⁹ R²⁰. A similar reaction sequence employing aWittig reaction can be used to synthesize alkenes where the double bondis not connected directly to the CR¹⁹ R²⁰ methylene group. Only theappropriate aldehyde (analog of (43) must be used to place the doublebond where necessary.

The synthetic scheme begins with the synthesis of (40). If X³ cannot bemade from condensation reactions as described previously, then X^(3') of(40) will be equal to X³ --(CH₂)_(y) -R²⁸. One may use the reactionsequences described in Scheme 7 to make these compounds. If X³ can bemade via condensation reactions, then a suitable precursor, X^(3') ispresent instead to make the synthesis easier. However, given the natureof the manipulations, sometimes the entire side-chain may be used whereX³ -(CH₂)_(y) -R²⁸ is present instead of X^(3') and X³ is made fromcondensation readtions. It is up to one familiar in the art to decidewhen to procede with the entire side-chain, or when to use a precursorcontaining X^(3').

Compound (40) may be synthesized by a number of routes, only some ofwhich are disclosed in Scheme 9. For example, if n'=0 and y=1 of(T)_(y), then the methanol side-chain may be alkylated onto the arylgroup T (or heterocyclic group) by the methods shown using formaldehydeor its equivalents, for example paraformaldehyde (G. Olah"Friedel-Crafts and Related Reactions," Interscience, New York, (1963)volume 2, pp. 597-640; N. S. Narasimhan, R. S. Mall, B. S. Kulkarni Tet.Lett., 1981,2797). When n'=1, then ethylene oxide or its equivalents maybe used as shown in Scheme 9 (J. March "Advanced Organic Chemistry,"Wiley-lnterscience, 1985, 3rd ed., p. 480; H. A. Patel, D. B. MacLeanCan. J. Chem. 1983, 61, 7). When n'=2 or more, then the appropriatealkyl side-chain may be attached via a Wittig reaction (to make anintermediate alkene) followed by reduction to the alkane. If them is noT group (y=0), then one has simple X^(3') substituted alcohols, many ofwhich are commercially available. X^(3') can be N-phthalimido, --NH-CBZ,carboxylic acid esters, --SO₃ CH₃, --SO₂ NH-t-Bu, -S-P where P is aprotecting group, etc., all of which can be easily transformed later oninto X³ groups (or compound (41)), the transformations being familiar toone skilled in the art. The original protected alcohol is deprotectedand converted to the bromide (42) as discussed elsewhere and previously.Conversion to the Wittig reagent (44) followed by reaction with aldehyde(43) (wherein X is a group suited for conversion later into L¹ such as aprotected alcohol, halogen, a protected nitrogen, etc.) yields alkene(45) (for a summary of the Wittig reaction and the Horner-Emmonsmodification thereto, see J. March "Advanced Organic Chemistry,"Wiley-Interscience, 1985, 3rd ed., p. 845-854). The sequence can also bereversed in that (43) could in theory be the Wittig reagent and (44)could be the aldehyde piece, both of which can be constructed by thechemistry mentioned in Scheme 9 and elsewhere in this disclosure.

The synthetic sequences leading to the incorporation of an alkynylside-chain are summarized in scheme 10. ##STR25##

A terminal alkyne is reacted with either NaNH₂, Grignard reagents, orBuLi to form the metal acetylide (J. March "Advanced Organic Chemistry,"Wiley-lnterscience, 1985, 3rd ed., p. 545), in this case alkynyl lithium(46) using n-BuLi. Reaction of this anion with ketone or aldehyde (47)yields alcohol (49) (see Ziegenbein in Viehe, "Acetylenes" MarcelDekker, New York, 1969, pp. 207-241; Ried, Newer Methods Prep. Org.Chem., 1968, 4, 95). If X³ can be formed via condensation reactions,then a suitable latent functionality X^(3') can be used instead asdiscussed previously. Subsequent elaboration yields X³ -containingalcohol (50). This alcohol may be esterified with im-(CH₂)_(n) -COOH (2)to yield sidechain A, subheading (h) where D is alkynyl. Likewise, asdiscussed previously to some extent, alcohol (49) may be esterified withcarboxylic acid (2) followed by elaboration to the X³ -containingside-chain denoted in (50). Esterification procedures are familiar toone skilled in the art. However, one may use a Mitsunobu-type procedurefor reacting alcohols (49) and (50) with carboxylic acid (2) under verymild conditions (O. Mitsunobu Synthesis 1981, 1) to yield the side-chaindescribed in A, subheading (h) , where D is alkynyl.

If the alkyne is not connected directly to CR¹⁹ R²⁰, but is foundsomewhere in the middle of the alkyl chain, then it may be synthesizedby the route depicted in going from compounds (51) to (56). The metalacetylide (52) (in this case we have arbitrarily chosen sodium as themetal), may be alkylated with bromide (51 ). The opposite may also bedone as shown with acetylide (53) reacting with bromide (54) to formacetylene (55). Intermediate (55) can then be deprotected and coupled tocarboxylic acid (2). Or first, the X^(3') of (55) is elaborated to X³,and then the alcohol deprotected to yield (56) which can be coupled tocarboxylic acid (2) in a manner similar to that used for (50). In all ofthese syntheses, if X³ cannot be formed by condensation reations (X³═CO, S,O, etc.) then the fully elaborated and protected (if necessary)side-chain must be used. Finally, if the acetylene portion is connecteddirectly to T (y is 1 ), then the synthesis follows that of going fromcompound (57) to (60). Thus, acetylene (57) is coupled in the presenceof a palladium catalyst to aryl or heteroaryl iodide or bromide (58) or(59) to yield the aryl or heteroaryl acetylene coupled product (W. Tao,S. Nesbitt, R. F. Heck J. Org. Chem. 1990, 55, 63; A. Walser, et al., J.Med. Chem. 1991, 34, 1440; T. Sakamoto, M. An-naka, Y. Kondo, H.Yamanaka Chem. Pharm. Bull. 1986, 34, 2754; N. A. Bumagin, V. V. Bykov,I. P. Beletskaya Izv. Akad. Nauk. SSSR. Ser. Khim. 1990, 2665; M. A. Dela Rosa, E. Vlarde, A. Guzman Syn. Comm. 1990, 20, 2059;Y. Kondo, H.Yamanaka Chem. Pharm. Bull., 1989, 37, 2933. Deprotection of the alcoholyields (60) which can be esterified as previously discussed.

Compounds where L¹ is amide, carbamate and urea may be made as discussedin Schemes 2-6 using the intermediates in Schemes 9 and 10.

Side-chains described in A, subheadings (i) through (o) may be made bythe procedures described in Schemes 9 and 10 together with thosementioned in the previous discussion in this application.

Side-chains described in A, subheading (p), namely --(CH₂)_(n) -L²-B-(T)_(y) -(B)_(y) -X² -(B)_(y) -R²⁸, where L² is a ketone carbonyl (L²═CO) may be synthesized by the methods shown in Scheme 11. ##STR26##

Alcohol (61) (described in U.S. Pat. No. 5,138,069)is oxidized bymethods familiar to one skilled in the art to aldehyde (62). Some ofthese methods include MnO₂ if n+1=1;PCC (pyridinium chlorochromate: E.J. Corey, J. W. Suggs Tet. Lett., 1975, 2647); pyridinium dichromate inmethylene chloride: E. J. Corey, G. Schmidt Tet. Lett., 1979, 399; Swernoxidation using DMSO and trifluoroacetic anhydride: K. Omura, A. K.Sharma, D. Swem, J. Org. Chem., 1976, 4 1, 957; Dess-Martin Periodinaneoxidation: D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4156 and J.P. Burkhart, N. P. Peet, P. Bey, Tet. Lett. 1988, 29, 3433; and Bobbittoxidation using 4-acetylamino-2,2,6,6-tetramethylpiperidinyl-1-oxyl andtoluenesulfonic acid: Z. Ma, J. M. Bobbitt, J. Org. Chem., 1991, 56,6110. Subsequent reaction of aldehyde (62) with a Grignard reagent or alithium reagent MCH₂ (CH₂)_(n'-1) -(T)_(y) -(B)_(y) -X^(2') (obtainedvia halogen-metal exchange, for example) yields alcohol (63). Here, asdiscussed previously, X^(2') is a suitable precursor to the fullyelaborated side-chain containing X², if X^(2') can be formed viacondensation reaction chemistry. If X^(2') cannot be formed viacondensation chemistry, then the whole side chain, namely MCH₂(CH₂)_(n'-1) -(T)_(y) -(B)_(y) -X² -(B)_(y) -R²⁸, is used where X² isprotected if necessary, with subsequent oxidation yielding ketone (65).Oxidation of alcohol (63) yields ketone (64) which may be elaborated asdiscussed previously to (65). Oxidation methods to the ketones includethose mentioned in the synthesis of aldehyde (62).

Another method for making ketone (65) involves alkylating ketone (67)(formed in an analogous manner to ketone (64) but employing methylGrignard or methyl lithium instead of MCH₂ (CH₂)_(n'-1) -(T)_(y)--(B)_(y) -X^(2')). Thus ketone (67) is reacted with lithiumdiisopropylamide (LDA) in THF at -78° C. to form enolate (68) whereM═Li. This enolate is then alkylated in the same reaction flask withXCH₂ (CH₂)_(n'-2) -(T)_(y) -(B)_(y) -X^(2') to yield ketone (64).

Side-chains described in A, subheading (p), namely --(CH₂)_(n) -L²-B-(T)_(y) -(B)_(y) -X² -(B)_(y) -R²⁸, where L² is an amide (L²═--NR^(11a) CO--), may be synthesized as depicted in Scheme 12. Amine(9) may be reacted with acid chloride (69) under Schotten-Baumannconditions as discussed previously to ##STR27## yield amide (70).Alternatively, diimide coupling of carboxylic acid (71) with amine (9)also yields amide (70), a procedure familiar to one skilled in the art,for example, the art of peptide synthesis. If X² can be made viacondensation reactions, then the partial assembly of the side-chain maybe carried out going through intermediates(72), (73) or (74) by the sameprocedures.

Scheme 13 shows the syntheses of amine (9) when n =0. Carboxylic acid(75) (prepared as in U.S. Pat. No. 5,138,069) is decarboxylated inrefluxing decane or another high boiling solvent to yield imidazole(76). Nitration under standard conditions yields nitroimidazole (77).Hydrogenation over palladium on carbon yields aminoimidazole (9a).Reductive amination to put on an R^(11a) group yields imidazole (9b)(for a review on reductive amination reactions, see Klyuev and Khidekel,Russ. Chem. Rev., 1980, 49, 14). ##STR28##

Side-chains described in A, subheadings (q) through (v) may besynthesized by the procedures described previously in this disclosure.

Side-chains described in A, subheading (w) wherein the alkene isconnected directly to L² (as opposed to having a alkyl spacer betweenthe alkene and L²) may be synthesized by the methods shown in Scheme 14.Other alkenes wherein the olefinic portion is located within the alkylchain may be synthesized by the methods already discussed in thisdisclosure. ##STR29##

Alcohol (41) can be oxidized by a variety of methods discussedpreviously, such as the Swern oxidation, pyridinium chlorochromate,pyridinium dichromate, etc., to yield aldehyde (78). Reaction of thisaldehyde with enolate (68) in an aldol reaction yields a,b-unsaturatedketone (79) (Aldol reaction: Nielsen and Houlihan, Org. React., 1968,16, 1-438). As discussed previously, if X³ can be formed viacondensation reactions, then the entire side-chain need not be fullyelaborated as in aldehyde (78). Here, X^(3') can be substituted for X³--(CH₂)_(y) -R²⁸, X^(3'60) being a latent functionality, which after thealdol condensation may be converted into X³ --(CH₂)_(y) -R²⁸. Anothersynthesis of ketone (79) would involve a Wittig reaction betweenaldehyde (78) and Wittig reagent (80), mimicking the chemistry presentedin Scheme 9. ##STR30##

Compounds where L² is --NR^(11a) CO-- may be synthesized by coupling(diimide coupling or Schotten-Baumann reaction, as discussed previously)amines 9, 9a, 21,21 a with a,b-unsaturated carboxylic acids (81) or (82)(or the corresponding acid chlorides), with subsequent elaboration ifnecessary. ##STR31##

Alkynes described in A, subheading (w) wherein the alkyne portion isconnected directly to the carbonyl group of L² in which L² is a ketone,may be synthesized by the methods shown in Scheme 15. ##STR32##

Acid chloride (83) (made from the corresponding carboxylic acid bysimply stirring with thionyl chloride or oxallyl chloride in an inertsolvent, procedures familiar to one skilled in the art and discussedpreviously) may be coupled with alkyne or alkynylstannane (84) or (85)in the presence of catalytic amounts of Cul-(Ph₃ P)₂ PdCl₂ andtriethylamine (for (84)) or Pd(II) or Pd(O) complexes (for (85)) toyield alkynyl ketone (86) (Y. Tohda, K. Sonogashira, N. HagiharaSynthesis (1977) 777; M. W. Logue, K. Teng J. Org. Chem. (1982) 47,2549). Other alkynes not directly connected to the ketone carbonyl canbe synthesized by procedures already discussed previously.

Alkynes described in A. subheading (w) wherein the alkyne portion isconnected directly to the carbonyl group of L² in which L² is --NR^(11a)CO--, may be synthesized by the methods shown in Scheme 16. ##STR33##

Amine (9) is coupled with alkynoic acids (88) or (89) to yield amide(91). Coupling methods include diimide, the Schotten-Baumann reactionwith the corresponding acid chlorides, both of which were discussedpreviously. The alkynoic acids may be synthesized from the correspondingalkynes via metallation (in this case with a Grignard reagent to makealkynemagnesium bromide (90)) and quenching with carbon dioxide in aninert solvent such as THF (H. Mayer Helv. Chim. Acta 1963, 46, 650; J.Wotiz, C. A. Hollingworth J. Am. Chem. Soc. 1956, 78, 1221).Intermediates in these metallations might have to be protected, in orderfor the reaction to succeed. For example, if X³ is a ketone, then itmust be protected, i.e., ketalized, a procedure familiar to one skilledin the art. Of course, intermediates like (92) and (87) (from Scheme 15)may be transformed to the fully elaborated side-chains as previouslydiscussed. Compounds wherein L² is --NR^(11a) CO--, and the alkyne islocated within the alkyl chain and not connected directly to thecarbonyl group of L² may by synthesized by methods already discussedpreviously in this application.

Side-chains described in A, subheadings (x) through (dd) may besynthesized by the procedures described previously in this disclosure.

When A of compounds of Formula (I) contains L³ (where L³ is --O--,--SO--, --NH--, or --NR^(11a) --), imidazoles (61, 93, 95, 98, 99) canbe used as starting materials in the synthesis of those side-chains.Such imidazoles can be prepared by the methods outlined in Scheme 17.Thus, treatment of alcohols (61,93) with thioacetic acid in the presenceof a Lewis acid catalyst (e.g. Znl₂) would provide (94), which uponsaponification with hydroxide ion (e.g. NaOH or KOH) in aqueous oraqueous alcohol solution, would give thiol (95) (J. Y. Gauthier Tet.Lett. 1986, 15). Imidazoles (61,93) can be converted to the chloridederivatives (96) by treatment with SOCl₂, for example, either neat or inan inert solvent, such as benzene or dichloromethane, between roomtemperature and the reflux temperature of the mixture. In turn, (96)could be reacted with azide anion (NAN₃, KN₃) in a suitable sovent(DMSO, DMF, NMP), to give (97), which when reduced with H₂ in thepresence of a catalyst, such as Pd/C, in alcohol solution, wouldgenerate amines (9, 9a, 99). These primary amines could, in turn, beconverted to secondary amines (21,21a, 98) through reductive amination(a method well-known to those skilled in the art) with an aldehyde,RCHO, and a reducing agent, such as NaCNBH₃ or NaBH(OAc)₃ (A. F.Abdel-Magrid; C. A. Maryanoff; K. G. Carson, Tet. Lett. 1990, 31, 5595)in alcohol solution. Alternatively, these secondary amines could begenerated directly from (96) by treatment with a primary amine, R^(11a)NH₂, in the presence of an acid scavenger (e.g. K₂ CO₃, Na₂ CO₃) in asuitable solvent (THF, DMF, CH₂ Cl₂, benzene). The best route to (21, 21a, 98) will be determined by the nature and availability of RCHO andR^(11a) NH₂, and the choice will be obvious to one skilled in the art.

Synthesis of imidazole (61) has been described here and elsewhere (U.S.Pat. No. 5,138,069). Imidazoles (93) may be prepared by methods shown inScheme 18. In the cases where m of (CH₂)_(m) --OH is two or three,esterification of carboxylic acids (2, 100;U.S. Pat. No. 5,138,069) withan alcohol (e.g. MeOH, EtOH) in combination with a mineral acid (e.g.hydrochloric or sulfuric) between room temperature and the reflux pointof the reaction mixture, followed by reduction with a hydride reducingagent (LiAlH₄, DlBAL-H, Red-Al®) in a suitable solvent (THF, ether)would yield (93, m=2, 3). On the other hand, Wittig reaction (a methodknown to one skilled in the art) of aldehyde (62) with a suitablyprotected phosphorane of the proper chain length (Agric. Bid. Chem.1984, 48, 1731; Synthesis 1985, 12, 1161 ) would yield an olefin.Hydrogenation over a catalyst such as Pd/C, followed by removal of theprotecting group with, for example, dilute mineral acid (HCl, H₂ SO₄) orcatalytic organic acid (p-TsOH, CSA) in a solvent such as THF or MeOH,would provide (93, m=3,4,5). ##STR34##

For subheadings (ee), (ff), (gg) and (hh), A may be synthesized byalkylating imidazole (61, 93, 95, 98, 99) with X--(CH₂)_(n') -(T)_(y)--(CH₂)_(y) -X² --(CH₂)_(y) -R²⁸, as in the specific case of (ee), asshown in Scheme 19. Likewise, for subheadings (if), (gg) and (hh),alkylation with the requisite alkylating agent would give A. In thisalkylation, X would be a halide or sulfonate group, and the reactionwould be run in an inert solvent such as THF, DMF, or DMSO between roomtemperature and the reflux temperature, in the presence of an acidscavenger, (e.g. Et₃ N or K₂ CO₃) or strong base (e.g. Nail or KH). Insome cases, it may prove advantageous to add a source of iodide ion tothe reaction (e.g. Nal, Kl, or n-Bu₄ N^(+I) ⁻). Such cases would beobvious to one skilled in the art. After the alkylation, to convertL^(3') =--S-- to L³ =--SO--, an oxidant such as hydrogen peroxide (R. L.Shriner; H. C. Struck; W. J. Jorison J. Am. Chem. Soc., 1930, 52, 2066)or sodium periodate (B. M. Trust, R. A. Kuns J. Org. Chem. 1974, 39,2648), or an organic peracid (H. Richtzenhain; B. Alfredson Chem. Ber.1953, 86, 142)or bromine/aqueous potassium hydrogen carbonate (J.Drabowicz; W. Midura; M. Mikolajczyk Synthesis, 1979, 39) can be used.As described previously in this disclosure, when X² in (ee) and (gg) isa condensable function, it may not be necessary to elaborate the entireside chain prior to alkylation. ##STR35##

A general method for the preparation of A groups (ii), (jj), and (kk) isshown in Scheme 20 for the particular case of (ii). Alkylation ofH-L^(3') -T-(B)y-X² -(B)y-R²⁸ (where H-L^(3') represents H-O-; H-S-, orH-NR^(11a) -) with chloride (96) in the presence of an acid scavenger orstrong base in an inert solvent with or without added iodide ion,followed by oxidation (when L³ is -SO-), would yield (102). When X² in(ii) and (kk) is a condensable function, it may not be necessary toelaborate the entire side chain prior to alkylation.

A possible method for preparation of A groups (ll) through (ss) is shownin Scheme 21 for the case of (ll). This method is analogous in allrespects to that described above for subheadings (ee) through (hh).Following alkylation, oxidation (when L³ is -SO-) would give (103). Asabove, when X⁶ (subheadings (ll) and (nn)) is a condensable function orX⁷ is present, it may not be necessary to elaborate the entire sidechain prior to alkylation. ##STR36##

Side-chains described in A, subheading (tt) and (uu) may be made by themethods shown in Schemes 22 and 23. ##STR37##

The 2-, 3-, and 4-pyridinecarboxylic acids, the 2-, 3-, and4-pyridineacetic acids and the 2-, 3-, and 4-pyridinepropanoic acids arereadily available from commercial sources or available with slightsynthetic manipulation from commercial sources as shown in Scheme 22.For example, pyridinecarboxaldehydes (104) (commercially available) mayundergo the Wittig reaction followed by saponification to yieldpyridinepropenoic acids (105). Hydrogenation using palladium on carbonin an alcohol catalyst yields pyridinepropanoic acid (107). All of thesetypes of reactions have been discussed previously. The pyridine alkanoicacids can then be hydrogenated with platinum oxide or rhodium on alumina(P. L. Ornstein, U.S. Pat. No. 4,968,678, issued Nov. 6, 1990) to yieldthe corresponding piperidine derivatives (111) (Scheme 23).Esterification by refluxing in methanol containing HCl (a procedurefamiliar to one skilled in the art) yields ester (112). Lithium aluminumhydride reduction yields alcohol (113) (P. L. Ornstein, ibid).

Condensing aminoalcohol (113) with the appropriately activated R²⁸ -X⁵or R³⁰ group yields compound (114). In this step, the nitrogen isreadily acylated or sulfonylated leaving the alcohol untouched, since itis more nucleophilic. For example, 4-(2-hydroxyethyl)piperidine, may bereadilly protected on the nitrogen exclusively with a carbamate (X⁵=-CO-O-) such as a BOC group by simply reacting with BOC₂ O andtriethylamine in DMF (M. E. Duggan, G. D. Hartman, N. Khle EuropeanPatent Application 512,829, published Nov. 11, 1992). Reaction of theaminoalcohol with alkyl- or arylchloroformates in the presence of anacid scavenger such as triethylamine at 0° C. also yields carbamatesselectively (W. Wiegreve, et al., Helv. Chim. Acta, 1974, 57, 301; F.Schneider, Helv. Chim. Acta, 1974, 57, 434; S. Umezawa, J. Antibiotics,1974, 27, 997). Amides (X⁹ =-CO-) may be made by simply stirring theamino alcohol with an appropriate ester (Y. Yamamoto, et al. Agri. Bio.Chem. 1985, 49, 1761) or with an acid chloride in the presence of anacid scavenger such as triethylamine at 0° C. (P. E. Sonnet et al., J.Org. Chem. 1980, 45, 3137) or with a carboxylic acid anhydride (D. A.Evans, J. M. Takacs Tet. Lett. 1980, 21, 4233; F. A. Davis, L. C.Vishwakarma Tet. Lett. 1985, 26, 3539). Sulfonamides (X⁵ =-SO₂ -) may bemade by stirring the aminoalcohol with a sulfonylchloride in thepresence of an acid scavenger such as triethylamine at 0° C. (H.Takahashi, et al. Chem. Pharm. Bull., 1991, 39, 260). Ureas (X⁵ =-CONH-)may be made by stirring the aminoalcohol with an isocyanate R²⁸ N═C═O(J. W. Kobzina, U.S. Pat. No. 4,065,291, issued Dec. 27, 1977). Ureas(X⁹ =-CONH-) may also be made by stirring the aminoalcohol with acarbamyl chloride R²⁸ NR^(11a) COCl in the presence of an acid scavengersuch as triethylamine at 0° C. (G. Hilgetag, A A. Martini "PreparativeOrganic Chemistry" John Wiley and Sons, New York, 1972, 469). The R³⁰groups may be also attached to the amino group by the methods discussedabove and previously using the appropriate starting material. Onceagain, all of these reactions selectively attach functionality to thenitrogen, but not to the alcohol.

The alcohol may be converted to a leaving group such as a tosylate orbromide or a NR^(11a) group as shown by methods previously discussedelsewhere in this application. These radicals then may be attached tothe L¹ or L² group to yield the side-chain described by A, subheading(tt) or (uu) by the same methods previously described in thisapplication. In addition, the entire side-chain need not be elaboratedbefore coupling it to the L¹ or L² group, but can be partially assembledas shown in the following discussion. Aminoalcohol (113) is selectivelyprotected (for example, with a BOC group as described above) to yield(118) and then is coupled to the L¹ or L² group. Deprotection and thencoupling with the activated X⁹ -R²⁸ or R³⁰ groups as previouslydescribed yields the side-chain described by A, subheading (tt) or (uu).Conversion of (118) to amine (119) by methods described previouslyfollowed by coupling to the L¹ or L² group, deprotection, and finallycoupling with the activated X⁹ or R³⁰ groups as previously describedyields the side-chain described by A, subheading (tt) and (uu) whereinL¹ =-CONR^(11a) -. Compounds represented by A, subheading (vv) to (ccc)may be synthesized by the procedures already described in thisapplication from the appropriate starting material and by methodsfamiliar to one skilled in the art.

The examples in Schemes 22 and 23 describe cases wherein v=2, or theheterocycles are all piperidines. For the pyrrolidine cases (v=1), thecorresponding reactions can be performed on proline or betaproline (H.Yuki, Y. Okamoto, Y. Kobayashi J. Polym Sci. Polym. Chem. Ed. 1979, 7,3867). Some starting materials, such as proline, are available inoptically active form and the chirality can be carried through to thefinal product. If starting materials are racemic, then a resolution mustbe performed somewhere in the synthesis to obtain the product inenantiomeric form. Resolving methods include crystallization orchromatographic separation on a chiral column.

Schemes 24 and 25 show two ways in which the bottom phenyl ring of themolecules is attached. The first way as shown in Scheme 24 involvesfirst, the connecting of the two phenyl rings together, in this case toform a biphenyl. This is then followed by the elaboration of A andfinishing off with the elaboration of the acidic moiety, namely R¹³. Itis also possible to elaborate R¹³ first, followed by A. It is alsopossible to partially elaborate A (we will refer to the precursor of Aas A'), then R¹³ and then finish with the final elaboration of A. All ofthese manipulations in relation to A have been previously described. Thesecond way exemplified in Scheme 25 involves the alkylation of a benzylonto the imidazole, followed by elaboration of A. Subsequent coupling ofthe second phenyl ring yields in this case a biphenyl system. Finally,the R¹³ group is elaborated into its final form. Here as above, the Agroup does not have to be fully elaborated and its full elaboration canbe put off to a later stage, depending on the compatability of thevarious groups in the molecule. ##STR38##

More specifically, we see in Scheme 24, that alkylation onto imidazole(120) (disclosed in U.S. Pat. No. 5,138,069, U.S. application Ser. No.07/544557) with a benzyl halide, tosylate, mesylate, etc. in an inertsolvent such as DMF in the presence of an acid scavenger such as K₂ CO₃yields benzylimidazole (121). The A' group can be fulther elaborated bymethods familiar to one skilled in the art into (CH₂)_(n) COOH to yield(2) which was seen earlier. However, for our present purposes, A' canequal CO₂ Me or compound (122). This ester group directs alkylationregioselectively as shown in U.S. application Ser. No. 07/544557. Suzukicoupling of bromobenzene (122) with boronic acid (123) (N. Miyaura, T.Yanagi, A. Suzuki, op. cit.) yields biphenyl (124). Note, that forsimplicity, the phenylboronic acid (123) is unsubstituted but may besubstituted with R² and R³ groups as specified in the scope of thisapplication. The synthesis of boronic acid (123) is shown in Scheme 26and will be discussed later. Saponification of the ester yields (125).Removal of the t-butyl group with trifluoroacetic acid yields carboxylicacid-sulfonamide (126). Alkylation with bromide (127) in an inertsolvent such as DMF in the presence of an acid scavenger such as K₂ CO₃yields ester (128). Sometimes, alkylation occurs both on the carboxylicacid and the sulfonamide. These two compounds are readily separated bychromatography. Finally acylation yields (129) as either asulfonylcarbamate, acylsulfonamide, or sulfonylurea, depending on theacylating agent. For example, acylating with an alkyl- orarylchloroformate in an inert solvent such as THF or pyridine with orwithout the use of an activating agent such as4-(N,N-dimethylamino)pyridine yields a sulfonylcarbamate (SO₂ -NH-CO₂R¹⁰). Doing the same with an acid chloride yields an acylsulfonamide(SO₂ -NH-COR¹⁰). Reacting sulfonamide (128) with an isocyanate yields asulfonylurea (SO₂ -NH-CO-NHR⁹) (Canadian patent application 2,058,198,published 1992/07/05, Hoechst Aktiengesellschaft). Finally, substitutionwith R⁹ -X where X is a leaving group yields a differently substitutedsulfonamide (SO₂ -NH-R⁹), these substitution reactions being eitherS_(N) 2 or aromatic or heteroaromatic substitution reactions, all ofwhich are familiar to one skilled in the art. The synthesis of these andother carboxylic acid isosteres is summarized in a Merck patentapplication (European Patent Application 400974, Dec. 5, 1990).

In Scheme 25, we see that regioselective alkylation with the brominatedanalog of (130) onto the imidazole aldehyde yields benzylimidazole (131). The aldehyde directs regioselective alkylation (U.S. application Ser.No. 07/544557). Grignard additon followed by oxidation of theintermediate alcohol yields ketone (132). Deprotonation with LDAfollowed by alkylation with benzylbromide (133) yields (134) in whichthe A group is fully elaborated. Attachment of the bottom phenyl ringvia Suzuki coupling (N. Miyaura, T. Yanagi, A. Suzuki, op. cit.) yieldsbiphenyl (135). Cleavage of the t-butyl group with TFA and acylationyields sulfonylcarbamate (136). In a similar fashion, theacylsulfonamide, sulfonylurea, and differently substituted sulfonamidecould have been made as described in the previous paragraph. Othercarboxylic acid isosteres within the scope of R¹³ can be substituted inplace of the ones discussed in Schemes 24 and 25 using the Suzuki arylcoupling methodology or any other coupling strategy discussed previouslyemploying the appropriate starting materials and the syntheticstrategies outlined in Schemes 24 and 25. Again, the syntheses of theseacid isosteres is discussed in a Merck patent application (EuropeanPatent Application 400974, Dec. 5, 1990). In the case where there is nobottom phenyl ring and therefore the imidazole is substituted by only abenzyl group and the benzyl group contains an acid isostere (R¹), thenthe synthetic strategy follows that of the biphenyl case withmanipulations being performed in a similar fashion at A' and R¹ (insteadof R¹³).

The β-ketoamides listed in Table 3 can be prepared following theprocedures outlined in Scheme 25a. Addition of vinyl Grignard to thebenzylimidazole followed by oxidation of the intermediate alcohol yieldsthe vinyl ketone. Michael addition of primary amine followed byacylation of the secondary amine with acyl chloride produces theβ-ketoamide. Suzuki coupling of the aryl bromide with the boronic acidgives the biphenyl. The acylsulfonamides, sulfonylurea and sulfonylcarbamates can be made in a similar fashion as described previously inthis section. ##STR39##

One may alkylate the imidazole nitrogen with a performed diaryl piece,such as the biphenyl moiety (37) shown in Scheme 26. ##STR40##

Sulfonamidoboronic acids (140) may be prepared by ortho-lithiation ofsulfonamide (139), followed by treatment with triisopropyl borate andhydrolysis, as shown in Scheme 27. The biphenyl sulfonamides (142) maybe prepared as described in EP479,479 or by aromatic coupling chemistry(Suzuki coupling), shown in Scheme 27. ##STR41##

The imidazole precursors shown in Scheme 26 and elsewhere in thisapplication may be prepared as described in U.S. Pat. Nos. 5,137,902 and5,138,069, in PCT U.S. application Ser. No. 90/03683 and in EuropeanApplication EP465,368 (see also Australian Patent AU-A-80163/91) and inU.S. application Ser. No. 07/544557, which are hereby incorporated byreference. Phenylimidazoles useful in preparing compounds of the Formula(I) where R⁸ is phenyl can be obtained as shown in Scheme 28. Thus,phenylboronic acids, available using standard methods, can be coupledwith iodoimidazoles (144) to yield phenylimidazoles (145). The boronicacids may contain substituents on the phenyl ring so as to allowconvenient preparation of the compounds of the present invention whereR⁸ is a substituted phenyl. ##STR42##

Compounds where L³ is -O₂ C- may be synthesized as shown in Scheme 29.##STR43## Thus, alcohol (93) may be acylated by a variety of methodsfamilair to one skilled in the art to yield ester (146) where the Rgroup represents any of the side-chains disclosed in A (ee) through (ss)and (vv), (ww), (bbb), and (ccc) in the scope of this application. Thesemethods include the Schotten-Baumann reaction, carbodiimide coupling,use of carbonyldiimidazole, etc. (for a summary on esterificationreactions, see J. March Advanced Organic Chemistry, 3rd ed., New York:John Wiley and Sons, pp. 348-351), which have been discussed previously.And again as discussed previously, the side-chain -O₂ C-R may beacylated as a whole completed unit or piece-wise depending on whetherX², X³, X⁴, and X⁵ may be formed via condensation reactions.

Aryloxyacetylimidazoles of Formula (I) such as (150) can be prepared asexemplified in Scheme 30. Thus, methyl ketone (67) may be converted tothe corresponding silyl enol ether using e.g. trimethylsilyltriflate/triethylamine. Bromination with NBS, followed by reaction withphenol (148) provides the phenoxyacetylimidazole (149), which may beconverted to compounds of Formula (I) as described in Scheme 25.##STR44##

The compounds of this invention and their preparation can be understoodfurther by the following examples which do not constitute a limitationof the invention. In these examples, unless otherwise indicated, alltemperatures are in degrees centigrade and parts and percentages are byweight.

EXAMPLE 1 ##STR45## Preparation of4-[(5-(2-benzoyl)benzyloxycarbonyl-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2-isoamyloxycarbonylaminosulfonylbipbenyl,potassium salt. ##STR46## Part A. Preparation of1-Bromo-4-bromomethyl-3-fluorobenzene.

1-Bromo-3-fluoro-4-methylbenzene (28.37 g, 0.15 mol, 1 eq),N-bromosuccinimide (26.72 g, 0.15 mol, 1 eq), azobisisobutyronitrile(1.44 g) and carbon tetrachloride (500 mL) were mixed and refluxedovernight. The mixture was filtered and washed with water (3×300 mL).The organic layer was dried (MgSO₄), and the solvent removed in vacuo toyield 37.88 g of an oil (75% product by NMR). NMR (CDCl₃) δ 4.45 (s,2H). This material was used in the subsequent step without furtherpurification. ##STR47##

Part B. Preparation of1-[(4-Bromo-2-fluorophenyl)methyl]-5-carbomethoxy-4-ethyl-2-n-propylimidazole.

5-Carbomethoxy-4-ethyl-2-n-propylimidazole (U.S. Pat. No. 5,137,902)(10.62 g, 54 mmol, 1 eq), 1-bromo-4-bromomethyl-3-fluorobenzene (19.58g, 54 mmol, 1 eq), potassium carbonate (7.48 g, 54 mmol, 1 eq), and DMF(200 mL) were mixed and stirred overnight at room temperature. Ethylacetate was added (500 mL) and the mixture was washed with water (3×300mL). The ethyl acetate layer was dried (MgSO₄), and the solvent removedin vacuo to yield 25.42 g of an oil. Flash chromatography in 75:25 to65:35 hexanes/ethyl acetate yielded 13.65 g of product as an amber oil.NMR (CDCl₃) δ 7.35-7.22 (m, 1H); 7.22-7.10 (m, 1H); 6.45 (t, 1H, J=7Hz);5.49 (s, 2H); 3.78 (s, 3H); 2.90 (q, 2H, J=7Hz); 2.59 (t, 2H, J=7Hz);1.70 (t of q, 2H, J=7,7Hz); 1.35-1.15 (m, 3H); 0.95 (t, 3H, J=7Hz).##STR48##

Part C. Preparation of 2-(t-butylamino)sulfonylphenyl boronic acid

To a 0° C. solution of 34.0 g (0.16 mol) ofbenzene-N-(t-butyl)sulfonamide in 500 mL of THF under N₂ was added 160mL (0.36 mol) of 2.25M n-butyllithium in hexane over 35 min., keepingthe temperature between 0°-2° C. The reaction mixture was allowed towarm to room temperature over 1.5 h, during which time a thickprecipitate formed. Triisopropylborate (46 mL, 0.20 mol) was added,keeping the temperature below 35° C. After 1 h, the reaction mixture wascooled, 1N HCl (260 mL) was added, and the mixture was stirred 30 min.After diluting with 520 mL of water, the mixture was extracted with 3×400 mL of ether. The combined organic extracts were extracted with 3×200 mL of 1N NaOH, and the aqueous extracts were acidified to pH 1 with6N HCl, then extracted with 3× 250 mL of ether. The ether extracts werewashed with 250 mL of brine, dried over MgSO₄ and the solvents wereremoved in vacuo to yield 45 g of a thick oil. After addition of toluene(45 mL), the mixture was agitated for 1 h on the rotary evaporator. Asmall quantity of solid formed, which was used to induce partialsolidification of the remaining crude product. Additional toluene (150mL) was added, and the mixture was reduced to 1/2 volume in vacuo,keeping the temperature from 0°-10° C. The resulting precipitate wascollected and washed with hexane, then dried under vacuum to give 24.6 g(60%) of the title compound as white crystals, m.p. 118°-119° C. ¹ H NMR(CDCl₃): δ 1.18 (s, 9H, CH₃); 5.13 (s, 1 H, NH), 6.29 (br s, 2H, OH);7.53 (m, 2H, ArH); 7.82 (d, 1H, ArH); 8.00 (d, 1H, ArH). ##STR49##

Part D. Preparation of2'-(N-t-butyl)sulfonamido-4-[(5-carbomethoxy-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluorobiphenyl.

1-[(4-Bromo-2-fluorophenyl)methyl]-5-carbomethoxy-4-ethyl-2-n-propylimidazole(5.00 g, 13 mmol, 1 eq) was dissolved in toluene (25 mL) and added to asuspension of potassium carbonate (3.61 g, 26 mmol, 2 eq),tetrabutylammonium bromide (0.42 g, 1.3 mmol, 0.1 eq),2-(t-butylamino)sulfonylphenyl boronic acid (5.03 g, 20 mmol, 1.5 eq) intoluene (25 mL). Water (10 mL) was then added followedtetrakistriphenylphosphine palladium (0) (0.75 g, 0.65 mmol, 0.05 eq).The mixture was slowly warmed to reflux temperature. After 16 hours, thereaction was worked up by adding water and extracting with methylenechloride (3×). The methylene chloride layers were combined and rinsedwith brine (1×). The organic layer was dried (MgSO₄), and the solventremoved in vacuo to yield 9.69 g of an amber oil Flash chromatography in75:25 to 1:1 hexanes/ethyl acetate yielded 5.89 g of an amber oil. NMR(CDCl₃) δ8.06 (d, 1H, J=8Hz); 7.47 (t, 1H, J=8Hz); 7.40 (t, 1H, J=8Hz)7.30-7.15 (m, 2H); 7.08 (d, 1H, J=8Hz); 6.58 (t, 1H, J=7Hz); 5.53 (s,2H); 3.70 (s, 3H); 3.60 (s, 1H); 2.83 (q, 2H, J=7Hz); 2.57 (t, 2H,J=7Hz); 1.65 (t of q, 2H, J=7,7 Hz); 1.20-1.10 (m, 3H); 0.91 (s, 9H);0.87 (t, 3H, J=7Hz). ##STR50##

Part E. Preparation of2'-(N-t-butyl)sulfonamido-4-[(5-carboxy-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluorobiphenyl.

2'-(N-t-butyl)sulfonamido-4-[(5-carbomethoxy-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluorobiphenyl(5.89 g, 11.4 mmol, 1 eq), 10 N NaOH (11.42 mL, 114 mmol, 10 eq), THF(25 mL), and methanol (enough to make a solution) were mixed and heatedat 50° C. overnight. The reaction was worked up by adding water andremoving the organic solvents in vacuo on a rotary evaporator. Methanolwas added and the pH was adjusted to about 2 with concentrated HCl. Themethanol was removed in vacuo and solids precipitated from the water.These solids were filtered, rinsed with ether and pumped under highvacuum to yield 4.45 g of a light yellow product: m.p. 223.5°-224.5° C.The solvent was further reduced from the filtrate yielding more productas a second crop: 1.13 g, m.p. 223.0°-224.0° C. NMR (DMSO-d₆) δ 8.01 (d,1H, J=7Hz); 7.58 (m, 2H); 7.35-7.20 (m, 2H); 7.14 (d, 1H, J=7Hz); 6.94(t, 1H, J=7Hz); 6.80 (s, 1H): 5.79 (s, 2H); 3.05-2.80 (m, 4H): 1.66 (tof q, 2H, J=7,7 Hz); 1/23 (t, 3H, J=7Hz); 0.95 (s, 9H); 0.88 (t, 3H,J=7Hz). ##STR51##

Part F. Preparation of4-[(5-Carboxy-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-sulfonamidobiphenyl.

2'-(N-t-Butyl)sulfonamido-4-[(5-carboxy-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluorobiphenyl(5.58 g) and trifluoroacetic acid (TFA) (75 mL) were mixed and stirredat room temperature overnight. The TFA was removed in vacuo and theresidue was dissolved in toluene. The toluene was removed in vacuo on arotary evaporator and this procedure was repeated again to remove alltraces of TFA. The residue was dissolved in ethyl acetate, dried(MgSO₄), and the solvent removed in vacuo to yield 6.92 g of an amberglass. NMR (DMSO-d₆) δ 8.10-7.95 (m, 1H): 7.70-7.50 (m, 2H); 7.37 (s,2H); 7.45-7.10 (m, 3H); 6.96 (t, 1H, J=7Hz); 5.84 (s, 2H); 3.10-2.80 (m,4H); 1.80-1.55 (m, 2H); 1.25 (t, 3H, J=7Hz); 0.91 (t, 3H, J=7Hz). Thematerial was used without additional purification in the next step.##STR52##

Part G. Preparation of4-[(5-(2-benzoyl)benzyloxycarbonyl-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-sulfonamidobiphenyl.

4-[(5-Carboxy-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-sulfonamidobiphenyl (6.92 g, 11 mmol, 1 eq),2-benzoylbenzyl bromide (obtained through bromination of2-methylbenzophenone by the procedure described in part A, except thatthe reaction was terminated after 1 h, and after work up, the unstableproduct was stored at 0° C.) (7.57 g, 22 mmol, 2 eq), potasium carbonate(1.52 g, 11 mmol, 1 eq) and DMF (75 mL) were mixed and stirredovernight. The reaction was worked up as described in Part B. Flashchromatography in 75:25 to 0:100 hexanes/ethyl acetate yielded 2.41 g ofan amber glass. FAB MS detects M⁺ +H=446.

Part H. Preparation of4-[(5-(2-benzoyl)benzyloxycarbonyl-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-isoamyloxycarbonylaminosulfonylbiphenyl,potassium salt.

4-[(5-(2-Benzoyl)benzyloxycarbonyl-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-sulfonamidobiphenyl(2.41 g, 3.77 mmol, 1 eq), 4-N,N-dimethylaminopyridine (1.84 g, 15.1mmol, 4 eq), isoamyl chloroformate (9.87 g, 15.1 mmol, 4 eq), pyridine(11 mL) and methylene chloride (50 mL) were mixed and stirred at roomtemperature. After 48 h, the reaction was complete. Methylene chloridewas added and the mixture was rinsed with water (1×), 10% citric acid(2×), and brine (1×) . The organic layer was seperated, dried (MgSO₄),and the solvent removed in vacuo to yield an amber oil. Flashchromatography in 1:1 hexanes/ethyl acetate to 100% ethyl acetateyielded 1.26 g of product as a tan colored glass. The product wasfurther titrated with 0.09M KOH and the water removed in vacuo followedby azeotroping with isopropanol to yield 1.20 g of an amber glass. NMR(CDCl₃) δ 8.07 (d, 1H, J=8Hz); 7.72 (d, 2H, J=8Hz); 7.60-7.00 (m, 12H0;6.36 (t, 1H, J=8Hz); 5.40 (s, 2H); 5.34 (s, 2H); 3.71 (t, 2H, J=7Hz);2.64 (q, 2H, J=7Hz); 2.56 (t, 2H, J=7Hz); 1.66 (t of q, 2H, J=7,7Hz);1.40 (m, 1H); 1.22 (q, 2H, J=7Hz); 1.07 (t, 3H, J=7Hz); 0.91 (t, 3H,J=7Hz); 0.71 (d, 6H, J=7Hz). Anal. calcd. for C₄₂ H₄₄ FN₃ OS.(H₂ O)₀.5 :C, 62.98; H, 5.54; F, 2.37; N, 5.25; S, 4.00. Found: C, 62.85; H, 5.54;F, 2.33; N, 5.09; S, 3.79.

EXAMPLE 2 ##STR53## Preparation of4-[(5-(2-benzoyl)benzyloxycarbonyl-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-(1H-tetrazol-5-yl)biphenyl.##STR54## Part A. Preparation of3-fluoro-4-methyl-2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl.

4-Bromo-2-fluorotoluene (5.00 g, 26 mmol, 1 eq),2-(N-triphenylmethyl-1H-tetrazol-5-yl)benzeneboronic acid (U.S. Pat. No.5,130,439) (14.29 g, 26 mmol, 1 eq), tetrakistriphenylphosphinepalladium(0) (1.53 g, 1.3 mmol, 0.05 eq), tetrabutylammonium bromide (0.42 g, 1.3mmol, 0.05 eq), 2M sodium carbonate (28.99 mL, 58 mmol, 2.23 eq) andtoluene (200 mL) were mixed and refluxed for 4 hours. The reaction wasworked up as in example 1, part D to yield 11.98 g of an amber glass.The glass was dissolved in ethyl acetate (25 mL) and triturated withether to yield 6.04 g of white solid product. The filtrate wasconcentrated and flash chromatographed in 9:1 hexanes/ethyl acetate toyield a further 3.72 g of white solid product. NMR (CDCl₃) δ 8.00-7.85(m, 1H); 7.55-7.40 (m, 2H); 7.40-7.10 (m, 10H); 7.00-6.70 (m, 9H); 2.18(s, 3H). ##STR55##

Part B. Preparation of4-bromomethyl-3-fluoro-2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl.

3-Fluoro-4-methyl-2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl (6.00g, 12 mmol) was brominated by the procedure described in example 1, partA to yield 7.45 g of an amber glass. NMR (CDCl₃) δ 4.39 (-CH₂ Br).##STR56##

Part C. Preparation of1-[(3-fluoro-2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl)methyl]-5-carbomethoxy-4-ethyl-2-n-propylimidazole.

4-bromomethyl-3-fluoro-2'-(N-triphenylmethyl- 1H-tetrazol-5-yl)biphenyl(7.45 g, 11.0 mmol, 1 eq) was alkylated onto5-carbomethoxy-4-ethyl-2-n-propylimidazole (2/16 g, 11.0 mmol, 1 eq) bythe procedure described in Example 1, part B to yield afterchromatography 2.53 g of an amber glass. NMR (CDCl₃) δ 8.00-7.80 (m,1H); 7.60-7.40 (m, 2H); 7.40-7.15 (m, 10H); 7.05-6.70 (m, 8H); 6.43 (t,1H, J=8Hz); 5.47 (s, 2H); 3.71 (s, 3H); 2.91 (q, 2H, J=7Hz); 2.48 (t,2H, J=7Hz); 1.75-1.55 (m, 2H); 1.26 (t, 3H, J=7Hz); 0.87 (t, 3H, J=7Hz).##STR57##

Part D. Preparation of1-[(3-fluoro-2'-(1H-tetrazol-5-yl)biphenyl)methyl]-5-carboxy-4-ethyl-2-n-propylimidazole.

1-[(3-Fluoro-2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl)methyl]-5-carbomethoxy-4-ethyl-2-n-propylimidazole(2.02 g, 2.92 mmol, 1 eq), 1.000N NaOH (5.85 mL, 5.85 mmol, 2 eq), THF(10 mL) and methanol (enough to solublize the mixture) were mixed andstirred at room temperature overnight. The reaction was incomplete andso another 2 equivalents of 1.000N NaOH were added and the mixturestirred for an additional 4 hours. The reaction was istill ncomplete andso another 4 equivalents of 10N NaOH were added and the mixture stirredovernight at room temperature. The reaction was worked up by addingwater and removing the organic solvents in vacuo. The remaining aqueousmixture was rinsed with ether (3×). Ethyl acetate was added to theaqueous mixture and the pH was adjusted to 2-3 with conc. HCl. Thelayers were seperated and the aqueous layer was extracted (2×) withethyl acetate. The ethyl acetate layers were combined, dried (MgSO₄),and the solvent removed in vacuo to yield a yellow glass. The glass wasstirred in ether to triturate 1.19 g of solid product. NMR shows thatboth the triphenylmethyl group and the methyl ester had been cleaved.NMR (DMSO-d₆) δ 7.80-7.40 (m, 4H); 7.00 (d, 1H, J=10 Hz); 6.87 (d, 1H,J=8Hz); 6.62 (t, 1H, J=8Hz); 5.64 (s, 2H); 2.83 (q, 2H, J=7Hz); 2.67 (t,2H, J=7Hz); 1.56 (t of q, 2H, J=7,7Hz); 1.15 (t, 3H, J=7Hz); 0.84 (t,3H, J=7Hz). FAB MS: (M⁺ +H)=435. ##STR58##

Part E. Preparation of1-[(3-fluoro-2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl)methyl]-5-carboxy-4-ethyl-2-n-propylimidazole.

1-[(3-Fluoro-2'-(1H-tetrazol-5-yl)biphenyl)methyl]-5-carboxy-4-ethyl-2-n-propylimidazole(960 mg, 2.21 mmol, 1 eq), triethylamine (0.34 mL, 2.43 mmol, 1.1 eq),triphenylmethyl chloride (678 mg, 2.43 mmol, 1.1 eq), and methylenechloride (10 mL) were mixed and stirred at room temperature. After 4hours, the reaction was worked up by adding water and seperating thelayers, The organic layer was dried (MgSO₄), and the solvent removed invacuo to yield 1.48 g of a white glass. Flash chromatography in 1:1hexanes/ethyl acetate to 100% ethyl acetate to 75:25 ethylacetate/isopropanol to yield 1.01 g of product as a white glass. NMR(CDCl₃) δ 7.80-7.60 (m, 1H); 7.50-7.05 (m, 12H); 6.94 (d, 6H, J=8Hz);6.80-6.40 (m, 3H); 5.70-5.30 (m, 2H); 2.90-2.70 (m, 2H); 2.40-2.10 (m,2H); 1.50 (m, 2H); 1.10-0.80 (m, 3H); 0.75-0.40 (m, 3H). ##STR59##

Part F. Preparation of4-[(5-(2-benzoyl)benzyloxycarbonyl-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl.

1-[(3-Fluoro-2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl)methyl]-5-carboxy-4-ethyl-2-n-propylimidazole(0.47 g, 0.694 mmol) was alkylated with 2-benzoylbenzyl bromide by theprocedure described in example 1, part G to yield after flashchromatography in 75:25 to 1:1 to 0:100 hexanes/ethyl acetate 440 mg ofan amorphous white product. NMR (CDCl₃) δ 7.95-7.85 (m, 1H); 7.75 (d,2H, J=8Hz); 7.60-7.15 (m, 19 H); 6.94 (d, 6H, J=8Hz); 6.90-6.70 (m, 2H);6.39 (t, 1H, J=8Hz); 5.38 (s, 2H); 5.35 (s, 2H); 2.77 (q, 2H, J=7Hz);2.41 (t, 2H, J=7Hz); 1.75-1.50 (m, 2H); 1.14 (t, 3H, J=7Hz); 0.84 (t,3H, J=7Hz).

Part G. Preparation of4-[(5-(2-benzoyl)benzyloxycarbonyl-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-(1H-tetrazol-5-yl)biphenyl.

4-[(5-(2-Benzoyl)benzyloxycarbonyl-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl(440 mg) and methanol (25 mL) were mixed and refluxed under nitrogen for3 hours. Silica gel was added and the solvent removed in vacuo. Theresidue was added to a flash chromatography column and quicklychromatographed in 1:1 hexanes/ethyl acetate to 80:20chloroform/methanol to yield 280 mg of product as an off-white glass.NMR (CDCl₃) δ 7.83 (d, 1H, J=7Hz); 7.68 (d, 2H, J=7Hz); 7.60-7.10 (m,10H); 6.80-6.60 (m, 2H); 6.27 (t, 1H, J=7Hz); 5.30 (s, 4H); 2.50 (m,2H); 2.33 (t, 2H, J=7Hz); 1.54 (t of q, 2H, J=7,7 Hz); 0.95-0.60 (m,6H). Anal. calcd. for C₃₇ H₃₃ FN₆ O₃ : C, 67.77; H, 5.53; F, 2.90; N,12.82. Found: C, 67.73; H, 5.15; F, 2.76; N, 12.62.

EXAMPLE 3 ##STR60## Preparation of1-((2'-((n-Butyloxycarbonyl-amino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-4-ethyl-5-(2-(2-phenoxyphenyl)ethylcarbonyl)-2-propyl-1H-imidazole.##STR61## Part A: Preparation of1-(2-fluoro-4-iodobenzyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxaldehyde

A solution of 2-fluoro-4-iodotoluene (47.28 g, 0.20 mol),N-bromosuccinamide (37.64 g, 0.21 mol) and azobisisobutyronitrile (3.65g, 0.02 mol) in CCl₄ (200 mL) was refluxed under N₂ overnight. Themixture was cooled, the solid was filtered off and washed with CCl₄. Thefiltrate was concentrated. The precipitated formed was filtered andwashed with hexane to give 13.92 g of 86% pure benzyl bromide. Themother liquid was concentrated to give 48.88 g of 60% pure benzylbromide. Both fractions were used without further purification in thenext step.

4-Ethyl-2-propyl-1H-imidazole-5-carboxaldehyde (6.32 g, 38.0 mmol),potassium carbonate (10.57 g, 76.5 mmol), and 2-fluoro-4-iodobenzylbromide (13.90 g of 86%, 38.0 mmol) were added together with 50 mL ofDMF. The reaction mixture was stirred at room temperature overnightunder N₂. The solvent was removed in vacuo and the residue waspartitioned between EtOAc and H₂ O. The two layers were separated. Theaqueous layer was extracted with EtOAc. The combined organic mixture waswashed with H₂ O and brine, dried over MgSO₄ and concentrated. The crudeproduct mixture was purified by flash chromatography (silica gel, 30-50%EtOAc/hexane) to yield 10.63 g orange oil (70%). MS m/e 401.0, [M+H]⁺ ;¹ H NMR (300 MHz, CDCl₃): δ 0.95 (t, 3H, CH₃), 1.32 (t, 3H, CH₃), 1.70(m, 2H, CH₂), 2.60 (m, 2H, CH₂), 2.82 (q, 2H, CH₂), 5.52 (s, 2H, CH2Ar),6.42 (t, 1H, ArH), 7.38 (d, 1H, ArH), 7.42 (d, 1H, ArH), 9.73 (s, 1H,CHO). ##STR62##

Part B: Preparation of1-(2-fluoro-4-iodobenzyl)-5-acetyl-4-ethyl-2-propyl-1H-imidazole

To a solution of1-(2-fluoro-4-iodobenzyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxaldehyde(16.52 g, 41.3 mmol) in THF (100 mL) was added methylmagnesium bromide(44.0 mL of 1.4/M in toluene/THF, 61.6 mmol) over 30 minutes. Thereaction mixture was stirred at room temperature for 1.5 h. It was thenquenched with 100 mL of 1N aqueous HCl. The mixture was extracted withCH₂ Cl₂, the organic solution was washed with H₂ O and brine, dried overMgSO₄, and concentrated to a yellow oil (16.87 g). The yellow oil wasdissolved in 400 mL of CH₂ Cl₂, and Manganese(IV) oxide (70.50 g, 811mmol) was added. The mixture was refluxed under N₂ overnight. Themixture was cooled. It was then filtered through celite and washed withCH₂ Cl₂. The CH₂ Cl₂ solution was concentrated and chromatographed onsilica gel with 50% EtOAc/hexane and 10% MeOH/CH₂ Cl₂ to give 4.70 g ofthe desired product and 6.87 g of the alcohol. MS m/e 415.0, [M+H]⁺ ; ¹H NMR (300 MHz, CDCl₃): δ 0.98 (t, 3H, CH₃), 1.35 (t, 3H, CH₃), 1.68 (m,2H, CH₂), 2.42 (s, 3H, CH₃) 2.58 (m, 2H, CH₂), 2.92 (q, 2H, CH₂), 5.45(s, 2H, CH₂ Ar), 6.28 (t, 1H, ArH), 7.35 (d, 1H, ArH), 7.42 (d, 1H,ArH). ##STR63##

Part C: Preparation of o-phenoxybenzyl alcohol

To a solution of o-phenoxybenzoic acid (19.0 g, 88.7 mmol) in THF (100mL) at 0° C. under N₂ was added BH₃.THF (133 mL, 1.0M in THF) over aperiod of 1 h, keeping the temperature below 5° C. The reaction mixturewas then stirred at room temperature for 2 h. It was quenched with H₂ O,then 1N aqueous HCl. The two layers were separated. The aqueous layerwas extracted with EtOAc. The combined organic mixture was washed withbrine, dried over MgSO, and concentrated to a light yellow oil (16.9 g).The crude product was used in the next step without furtherpurification. MS m/e 183.1, [M+H-H₂ O]⁺ ; ¹ H NMR (300 MHz, CDCl₃): δ2.08 (t, 1H, OH), 4.76 (d, 2H, CH₂ Ar), 6.82-7.48 (m, 9H, ArH).##STR64##

Part D: Preparation of o-phenoxybenzyl iodide

To a solution of o-phenoxybenzyl alcohol (5.0 g, 25 mmol) andtriethylamine (10.4 mL, 75 mmol) in CH₂ Cl₂ (50 mL) at 0° C. was addedmethanesulfonyl chloride (3.9 mL, 50 mmol). The reaction mixture wasstirred at 0° C. for 1 h and then at room temperature for 3.5 h. Themixture was washed H₂ O and brine. It was filtered through phaseseparator paper and concentrated to a yellow oil. The oil was thendissolved in 50 mL of acetone, and sodium iodide (7.5 g, 50 mmol) wasthen added. The mixture was stirred at more temperature overnight.Hexane was added to the mixture. The solid was filtered off. Thefiltrate was concentrated and chromatographed on silica gel with hexaneto give 5.22 g of yellow oil. MS m/e 183.1, [M+H-HI]⁺ ; ¹ H NMR (300MHz, CDCl₃): δ 4.52 (s, 2H, CH₂ Ar), 6.82-7.48 (m, 9H, ArH). ##STR65##

Part E: Preparation of 1-(2-fluoro-4-iodobenzyl)-4-ethyl-5-(2-(2-phenoxyphenyl)ethylcarbonyl)-2-propyl- 1H-imidazole

1-(2-fluoro-4-iodobenzyl)-5-acetyl-4-ethyl-2-propyl- 1H-imidazole (5.52g, 13.3 mmol) was dissolved in 50 mL of THF. The mixture was cooled at0° C. under N₂ and lithium diisopropylamide (7.3 mL of 2M in THF, 14.6mmol) was added. After stirred at 0° C. for 15 minutes, a solution ofo-phenoxybenzyl iodide (5.22 g, 16.8 mmol) in THF (15 mL) was added. Thereaction mixture was warmed up to room temperature and stirred for 2 h.The mixture was partitioned between EtOAc and H₂ O. The two layers wereseparated. The aqueous layer was extracted with EtOAc. The combinedorganic solution was washed with brine, dried over MgSO₄. It wasconcentrated and chromatographed on silica gel with 10-50% EtOAc/hexaneto yield 2.35 g of the desired product. MS m/e 597.2, [M+H]⁺ ; IR (KBr):1646 cm⁻¹ for CO; ¹ H NMR (300 MHz, CDCl₃): δ 0.95 (t, 3H, CH₃), 1.22(t, 3H, CH₃), 1.65 (m, 2H, CH₂), 2.57 (m, 2H, CH₂), 2.82 (q, 2H, CH₂),2.98 (m, 2H, CH₂), 3.10 (m, 2H, CH₂) 5.42 (s, 2H, CH₂ Ar), 6.22 (t, 1H,ArH), 6.82 (d, 1H, ArH), 6.90 (d, 2H, ArH), 7.02 (m, 2H, ArH), 7.18 (d,1H, ArH), 7.22 (m, 2H, ArH), 7.30 (m, 2H, ArH), 7.40 (d, 1H, ArH).##STR66##

Part F: Preparation of1-((2'-((t-butylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-4-ethyl-5-(2-(2-phenoxyphenyl)ethylcarbonyl)-2-propyl-1H-imidazole

1-(2-fluoro-4-iodobenzyl)-4-ethyl-2-propyl-1H-imidazole-5-phenoxyphenethylketone (2.35 g, 3.90 mmol), 2-(t-butylamino)sulfonylphenyl boronic acid(1.52 g, 5.85 mmol), and soduim carbonate (10 mL of 2M aqueoussolution), and tetrabutylammonium bromide (65 mg, o.20 mmol) were addedtogether with 50 mL of toluene. Tetrakis(triphenylphosphine)palladium(O) (0.23 g, 0.20 mmol) was added. The mixture was refluxedunder N₂ overnight. The solvent was removed in vacuo and the residue waspartitioned between H₂ O and CH₂ Cl₂. The aqueous layer was extractedwith CH₂ Cl₂, and the combined organic solution was washed with brine,dried over MgSO₄ and concentrated. The crude product was purified byflash column chromatography (silica gel, 30% EtOAc/hexane) to give 1.92g of light yellow foam (72%). MS m/e 682.5, [M+H]⁺ ; ¹ H NMR (300 MHz,CDCl₃): δ 0.96 (t, 3H, CH₃), 0.98 (t, 9H, CH₃), 1.27 (t, 3H, CH₃), 1.69(m, 2H, CH₂), 2.60 (t, 2H, CH₂), 2.85 (q, 2H, CH₂), 2.97 (m, 2H, CH₂),3.13 (m, 2H, CH₂), 3.58 (s, 1H, NH), 5.57 (s, 2H, CH₂ Ar), 6.60 (t, 1H,ArH), 6.86 (d, 1H, ArH), 6.92 (d, 2H, ArH), 7.05 (d, 2H, ArH), 7.16 (m,2H, ArH), 7.26 (m,5H, ArH), 7.55 (m, 2H, ArH), 8.16 (m, 1H, ArH).##STR67##

Part G: Preparation of1-((2'-(aminosulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-4-ethyl-5-(2-(2-phenoxyphenyl)ethylcarbonyl)-2-propyl-1H-imidazole

1-((2'-((t-butylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-phenoxyphenethylketone (1.92 g, 2.8 mmol) was refluxed with 15 mL of trifluoroaceticacid under N₂ for 2 h. The solvent was removed in vacuo. The residue wasdissolved in CH₂ Cl₂, and washed with aqueous NaHCO₃ and brine. Theorganic solution was filtered through phase separator paper and thenconcentrated to a light yellow foam (1.84 g). MS m/e 626.0, [M+H]⁺ ; ¹ HNMR (300 MHz, CDCl₃): δ 0.95 (t, 3H, CH₃), 1.26 (t, 3H, CH₃), 1.69 (m,2H, CH₂), 2.60 (t, 2H, CH₂), 2.84 (q, 2H, CH₂), 2.97 (m, 2H, CH₂), 3.12(m, 2H, CH₂), 4.20 (s, 2H, NH₂), 5.57 (s, 2H, CH₂ Ar), 6.65 (t, 1H,ArH), 6.85 (d, 1H, ArH), 6.92 (d, 2H, ArH), 7.01-7.37 (m, 9H, ArH), 7.58(m, 2H, ArH), 8.15 (d, 1H, ArH).

Part H: Preparation of1-((2'-((n-Butyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-4-ethyl-5-(2-(2-phenoxyphenyl)ethylcarbonyl)-2-propyl-1H-imidazole

1-((2'-(aminosulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-phenoxyphenethylketone (1.84 g, 2.90 mmol) was dissolved in 50 mL of CH₂ Cl₂. To themixture was added 4-N,N-dimethylaminopyridine (0.40 g, 3.19 mmol),pyridine (2 mL), and n-Butyl chloroformate (1.48 mL, 11.60 mmol). Thereaction mixture was allowed to stir at room temperature under N₂ for 98h.. The mixture was washed with 10% aqueous citric acid and brine. Theorganic solution was filtered through phase separator paper andconcentrated. It was then chromatographed on silica gel (eluted with25-100% EtOAc/CH₂ Cl₂ ) to give 1.48 g light yellow foam. MS m/e 725.0,[M+H]⁺ ; ¹ H NMR (300 MHz, CDCl₃) δ 0.84 (t, 3H, CH₃), 0.97 (t, 3H,CH₃), 1.10-1.32 (m, 5H, CH₃,CH₂), 1.47 (m, 2H, CH₂), 1.71 (m, 2H, CH₂),2.63 (t, 2H, CH₂), 2.83 (q, 2H, CH₂), 2.99 (m, 2H, CH₂), 3.12 (m, 2H,CH₂), 3.98 (t, 2H, OCH₂), 5.58 (s, 2H, CH₂ Ar), 6.62 (t, 1H, ArH),6.81-7.37 (m, 12H, ArH), 7.60 (m, 2H, ArH), 8.25 (d, 1H, ArH).

EXAMPLE 4 ##STR68## Preparation of4-[(5-(2-trifluoromethylphenyl)methylaminocarbonyl-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-isoamyloxycarbonylaminosuifonylbiphenyl,potassium salt ##STR69## Part A. Preparation of4-[(5-(2-trifluoromethylphenylmethyl)aminocarbonyl-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-(N-t-butyl)sulfonamidobiphenyl.

A solution of (2-trifluoromethyl)benzylamine (0.22 mL, 1.6 mmol),dicyclohexylcarbodiimide (0.33 g, 1.6 mmol), and 1-hydroxybenzotriazolehydrate (0.22 g, 1.6 mmol) in acetonitrile (30 mL) was stirred under N₂for 15 minutes.2'-(N-t-butyl)sulfonamido-4-[(5-carboxy-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluorobiphenyl(0.75 g, 1.6 mmol) was then added and the reaction stirred at roomtemperature overnight. The reaction was filtered and the filtrate thenevaporated. The residue was taken up in CH₂ Cl₂, washed with water,dried over MgSO₄, filtered and evaporated. The residue was thenchromatographed with 50% ethyl acetate in hexane to yield 0.95 g of awhite product. NMR (CDCl₃) δ 8.09 (d, 1H), 7.60-7.10 (m, 9H), 6.75 (t,1H), 6.04 (m, 1H), 5.51 (m, 1H), 4.67 (d, 2H), 2.63 (m, 2H), 2.53 (m,2H), 1.60 (m, 2H), 1,18 (m, 3H), 0.90 (m, 12H)

Part B. Preparation of4-[(5-(2-trifluoromethylphenyl)methylaminocarbonyl-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-isoamyloxycarbonylaminosulfonylbiphenyl,potassium salt.

4-[(5-(2-trifluoromethylphenyl)methylaminocarbonyl-4-ethyl-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-(N-t-butyl)sulfonamidobiphenylwas converted to product by using the methods of Example 1, parts G andH. The reactions yielded 0.33 g of product. NMR (CDCl₃) δ 8.02 (d, 1H),7.64-7.05 (m, 9H), 6.56 (t, 1H), 6.20 (m, 1H), 5.33 (s, 2H), 4.65 (d,2H), 3.77 (t, 2H), 2.67 (q, 2H), 2.54 (m, 2H), 1.65 (m, 2H), 1.40 (m,1H), 1.21 (m, 3H), 0.95 (t, 3H), 0.76 (d, 6H).

EXAMPLE 5 ##STR70## Preparation of N-butyl,N-benzyl-2-(aminocarbonyl)ethynylmethyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate##STR71## Part A. Preparation of t-Butyldimethylsilyl propargyl ether

To a solution of 5.82 mL of propargyl alcohol in 20 mL of pyridine and30 mL of CH₂ Cl₂ was added 0.122 g of DMAP and 16.88 g of TBDMSCl in aN₂ atmosphere. After stirring 3 days, the reaction was poured into 100mL of 1N HCl, and diluted with CH₂ Cl₂. The layers were separated andthe organic layer washed with 100 mL of 1N HCl (2×), 10% NaHCO₃, H₂ Oand brine and dried (MgSO₄). Filtration and concentration provided 15.07g of an oil which was used without purification.

¹ H-NMR (CDCl₃) δ 4.19 (s, 2H), 2.25 (s, 1H), 0.80 (s, 9H), 0.03 (s, H).##STR72##

Part B. Preparation of 4-(t-Butyldimethylsilyloxy)-2-butynoic acid

To an ice-cold solution of 13.71 g t-butyldimethylsilyl propargyl etherin 160 mL anhydrous THF was added dropwise 35 mL EtMgBr (3M in Et₂ O) ina N₂ atmosphere. After completing the addition, the reaction was stirred45 minutes at room temperature. Pellets of dry ice were then addedslowly until the reaction became cold and carboxylate salt precipitated.Stirring at room temperature was continued overnight. The reaction wasconcentrated to dryness and the residue partitioned between H₂ O and Et₂O and the organic extract discarded. The aqueous solution was acidifiedto pH 2 with 6N HCl and immediately extracted with EtOAc. The organiclayer was washed with 10% NaHCO₃, H₂ O, and brine and dried (MgSO₄).Filtration and concentration provided 13.56 g of product which was usedwithout purification. ¹ H-NMR (CDCl₃) δ 10.6 (s, 1H), 4.3 (s, 2H), 0.80(s, 9H), 0.03 (s, 6H). ##STR73##

Part C. Preparation of N-butyl,N-benzyl-4-(t-butyldimethylsilyloxy)-2-butynamide

In a flame-dried flask, 0.279 g NaH (80% dispersion in mineral oil) waswashed with 5 mL pentane (3×) while maintaining a N₂ atmosphere. The NaHwas then suspended in 50 mL anhydrous benzene to which was addeddropwise at room temperature a solution of 2.0 g4-(t-butyldimethylsilyloxy)-2-butynoic acid in 45 mL benzene. After 45minutes 4.05 mL (COCl)₂ was added and the reaction stirred overnight.The mixture was filtered through glass fiber paper to remove NaCl andthe clear filtrate concentrated. The residue was dissolved in 95 mLbenzene and concentrated again. The crude residual acid chloride wasused immediately as described below.

To an ice-cold solution of 0.350 g butylbenzylamine and 0.447 mLdiisopropylethylamine in 11 mL dry benzene under N₂ was added a solutionof the above acid chloride in 11 mL benzene. After stirring overnightwith gradual warming to room temperature, the reaction was poured intoH₂ O and extracted with Et₂ O (3×). The combined organic extracts werewashed with brine and dried (MgSO₄). Filtration and concentrationprovide crude product which was purified by flash chromatography with a10%-15% Et₂ O/hexanes gradient to give 0.39 g of product.

¹ H-NMR (CDCl₃) δ 7.30-7.15 (m, 5H), 4.7 and 4.55 (s, 2H), 4.4 and 4.38(s, 2H), 3.40 and 3.22 (t, 2H), 1.6-1.4 (m, 2H), 1.30-1.18 (m, 2H),0.90-0.75 (m, 12H), 0.03 and 0.01 (s, 6H). [product is a mixture ofrotamers] ##STR74##

Part D. Preparation of N-butyl, N-benzyl-4-hydroxy-2-butynamide

To an ice-cold solution of 0.61 g N-butyl,N-benzyl-4-(t-butyldimethylsilyl-oxy)-2-butynamide in 17 mL CH₃ CN underN₂ was added dropwise 0.61 mL 48% HF. The reaction was stirred 2 hoursat ice bath temperature, then neutralized by the careful addition of 10%NaHCO₃. The reaction was transferred to a separatory funnel, dilutedwith H₂ O and extracted with Et₂ O. The combined organics were washedwith 10% NaHCO₃, H₂ O, and brine and dried (MgSO₄). Filtration andconcentration provided 0.27 g of product which was used as is.

¹ H-NMR (CDCl₃) δ 7.40-7.20 (m, 5H), 4.80 (s, 1H), 4.60 (s, 1H),4.43-4.37 (dd, 2H), 4.20-4.05 (bs, 1H), 3.50-3.40 (t, 2H), 3.30-3.20 (t,2H), 1.60-1.40 (m, 2H), 1.40-1.20 (m, 2H), 0.95-0.80 (2t, 3H). [productis a mixture of rotamers] ##STR75##

Part E. Preparation of N-butyl, N-benzyl-4-bromo-2-butynamide

To an ice-cold solution of 0.27 g N-butyl,N-benzyl-4-hydroxy-2-butynamide in 11 mL CH₂ Cl₂ in a N₂ atmosphere wasadded 0.582 g CBr₄. After stirring 10 min, 0.345 g Ph₃ P was added andthe reaction stirred overnight with gradual warming to room temperature.The reaction was diluted with H₂ O and extracted with CH₂ Cl₂. Thecombined organics were washed with brine and dried (Na₂ SO₄).Filtration, concentration, and flash chromatography using a 20%-40% Et₂O/hexanes gradient gave 0.26 g of product.

¹ H-NMR (CDCl₃) δ 7.40-7.20 (m, 5H), 4.75 and 4.60 (s, 2H), 4.21 and4.00 (d, 1H), 3.42 and 3.26 (t, 2H), 1.50 amd 1.30 (m, 2H), 0.98-0.83(2t, 3H). [product is a mixture of rotamers] ##STR76##

Part F. Preparation of N-butyl, N-benzyl-2-(aminocarbonyl)ethynylmethyl4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylate

To a solution/suspension of 0.55 g4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl-]methyl]imidazole-5-carboxylicacid, 0.26 g N-butyl, N-benzyl-4-bromo-2-butynamide, and 0.12 g powderedK₂ CO₃ in 3 mL DMF was added in one portion 0.14 g KI. The reaction wasstirred 3 h at room temperature under N₂, then partitioned between 8 mLH₂ O and 40 mL EtOAc. The organic extract was washed once with ice-cold0.1N Na₂ S₂ O₃, H₂ O, and brine, and dried (MgSO₄). Filtration,evaporation and flash chromatography using a 30%-50% EtOAc/hexanesgradient provided 0.65 g of product.

¹ H-NMR (CDCl₃) δ 7.87 (br d, 1H), 7.50-7.40 (m, 2H), 7.38-7.16 (m, 15H), 7.10-7.00 (m, 2H), 7.00-6.90 (m, 6H), 6.78-6.65 (m, 2H), 5.41 and5.35 (s, 2H), 4.81 and 4.79 (s, 2H), 4.70 and 4.60 (s, 2H), 3.40 and3.25 (t, 2H), 2.95 and 2.83 (q, 2H), 1.75-1.60 (m, 2H), 1.57-1.40 (m,2H), 1.35-1.14 (m, 5H), 0.95-0.80 (2t, 6H). [product is a mixture ofrotamers]

Part G. Preparation of N-butyl, N-benzyl-2-(aminocarbonyl)ethynylmethyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate

To a solution of 0.55 g N-butyl, N-benzyl-3-carboxamido-2-propynyl4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylate in 14 mL MeOH at roomtemperature was added 5 drops of 6N HCl. After stirring overnight, thereaction was evaporated to dryness and the residue purified by flashchromatography using a 0%-5% MeOH/CHCl₃ gradient to provide 0.36 g ofproduct.

MS (NH₃ -Cl) 644.4 (M+H)⁺, 680.4 (M+NH₄)⁺.

EXAMPLE 6 ##STR77## Preparation ofN,N-diphenyl-2-(aminocarbonyl)ethynylmethyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate##STR78## Part A. Preparation of Ethyl4-(t-butyldimethylsilyloxy)-2-butynoate

To a solution/suspension of 2.0 g of4-(t-butyldimethylsilyloxy)-2-butynoic acid and 1.48 g Na₂ CO₃ in 37 mLDMF under N₂ was added slowly 1.58 mL Et₂ SO₄. After stirring overnight,the reaction was diluted with EtOAc and washed several times with H₂ O.The organic extract was then washed with brine and dried over MgSO₄.Filtration, evaporation and flash chromatography with a 5%-10% Et₂O/hexanes gradient provided 1.58 g of pure product.

¹ H-NMR (CDCl₃) δ 4.3 (s, 2H), 4.10 (q, 2H), 1.20 (t, 3H), 0.80 (s, 9H),0.03 (s, 6H). ##STR79##

Part B. Preparation of N,N-diphenyl-4-(t-butyldimethylsilyloxy)-2-butynamide

To a solution of 1.4 mL Me₃ Al (2.0M in hexanes) in 3.6 mL anhydrous CH₂Cl₂ under N₂ was added 0.49 g of diphenylamine in one portion. Afterstirring 30 min, 0.35 g ethyl 4-(t-butyldimethylsilyloxy)-2-butynoate in0.4 mL CH₂ Cl₂ was added dropwise. The reaction was stirred overnight atroom temperature, then heated in an oil bath at 35° overnight. Thereaction was quenched by the addition of a few drops of 1N HCl, dilutedwith H₂ O, and extracted with CH₂ Cl₂. The combined organics were withH₂ O and brine and dried over Na₂ SO₄. Filtration, evaporation, andflash chromatography with a 10-15% Et₂ O/hexanes gradient provided 0.31g of product.

¹ H-NMR (CDCl₃) δ 7.50-7.20 (m, 10H), 4.25 (s, 2H), 0.84 (s, 9H), 0.02(s, 6H). ##STR80##

Part C. Preparation of N, N-diphenyl-4-hydroxy-2-butynamide

By employing the procedure described in Example 5, Part D, there wasobtained from 0.91 g N,N-diphenyl-4-(t-butyldimethylsilyloxy)-2-butynamide 0.45 g of pureproduct.

¹ H-NMR (CDCl₃) δ 7.43-7.15 (m, 10H), 4.10 (s, 2H), 3.05 (br s, 1H).##STR81##

Part D. Preparation of N, N-diphenyl-4-bromo-2-butynamide

By employing the procedure described in Example 5, Part E, there wasobtained from 0.45 g N, N-diphenyl-4-hydroxy-2-butynamide 0.54 g ofproduct.

¹ H-NMR (CDCl₃) δ 7.43-7.2 (m, 10H), 4.0 and 3.78 (s, 2H). [product is amixture of rotamers] ##STR82##

Part E. Preparation of N-butyl, N-benzyl-2-(aminocarbonyl)ethynylmethyl4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylate

By employing the procedure described in Example 5, Part F, there wasobtained from 0.56 g N, N-diphenyl-4-bromo-2-butynamide 1.16 g of pureproduct.

¹ H-NMR (CDCl₃) δ 7.90-7.85 (m, 1H), 7.44-7.39 (m, 2H), 7.37-7.17 (m,20H), 7.15-7.02 (m, 2H), 6.95-6.85 (m , 6H), 6.80-6.78 (m, 2H), 5.40 (s,2H), 4.60 (s, 2H), 2.79 (q, 2H), 2.58 (t, 2H), 1.65 (m, 2H), 1.22 (t,3H), 0.90 (t, 3H).

Part F. Preparation of N-butyl, N-benzyl-2-(aminocarbonyl)ethynylmethyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate

By employing the procedure described in Example 5, Part G, there wasobtained from 1.16 g N, N-diphenyl-3-carboxamido-2-propynyl4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylate0.60 g of pure product.

¹ H-NMR (CDCl₃) δ 7.83 7.80 (m, 1H), 7.60-7.50 (m, 2H), 7.44-7.40 (m,1H), 7.40-7.20 (m, 8H), 7.20-7.06 (m, 4H), 6.82-6.78 (m, 2H), 5.40 (s,2H), 4.61 (s, 2H), 2.63 (q, 2H), 2.42 (t, 2H), 1.75-1.60 (m, 2H), 1.05(t, 3H), 0.91 (t, 3H).

EXAMPLE 7 ##STR83## Preparation of N-phenyl-2-(aminocarbonyl)ethyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate##STR84## Part A. Preparation of N-phenyl-2-(aminocarbonyl)ethyl4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylate

To a solution/suspension of 0.66 g4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylicacid, 0.23 g 2-bromo-N-phenylpropionamide, and 0.15 g K₂ CO₃ in 7 mL ofDMF was added 0.17 g of KI. The reaction was stirred 10 minutes at roomtemperature, then heated in a N₂ atmosphere at 70° C. overnight. Thereaction was partitioned between H₂ O and EtOAc, and the organic extractwashed with brine and dried with MgSO₄. Filtration, concentration, andflash chromatography with a 10-60% EtOAc/hexanes gradient provided 0.35g of pure product.

¹ H-NMR (CDCl₃) δ 8.70 and 7.98 (br s, 1H), 7.85 (m, 1H), 7.50-7.40 (m,4H), 7.37-7.20 (m, 13H), 7.11-7.00 (m, 3H), 6.99-6.91 (m, 5H), 6.80-6.77(m, 2H), 5.40 (s, 2H), 5.35 and 4.28 (q, 1H), 2.99 (q, 2H), 2.55 (t,2H), 1.78-1.60 (m, 2H), 1.53 and 1.48 (d, 3H), 1.37 (t, 3H), 0.87 (t,3H).

Part B. Preparation of N-phenyl-2-(aminocarbonyl)ethyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate

A solution of 0.05 g N-phenyl-2-(aminocarbonyl)ethyl4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylate in 2.5 mL MeOH wasrefluxed overnight under N₂. The reaction was evaporated to dryness andthe residue immediately purified by flash chromatography with 0-5%MeOH/CHCl₃ gradient to give 0.0226 g of pure product.

¹ H-NMR (CDCl₃) δ 8.10 (br s, 1H), 7.88 (m, 1H), 7.60-7.45 (m, 2H),7.40-7.23 (m, 3H), 7.20-7.10 (m, 2H), 7.09-6.96 (m, 3H), 6.81-6.75 (m,2H), 5.40 (s, 2H), 5.27 (q, 1H), 2.72 (q, 2H), 2.40 (t, 2H), 1.68-1.60(m, 2H), 1.52 (d, 3H), 1.08 (t, 3H), 0.88 (t, 3H).

EXAMPLE 8 ##STR85## Preparation of N-butyl,N-benzyl-4-(aminocarbonyl)propyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate##STR86## Part A. Preparation of N-butyl, N-benzyl-4-hydroxy-butanamide

To a solution of 23 mL of Me₃ Al (2.0M in hexanes) in 24 mL of CH₂ Cl₂was added in a N₂ atmosphere 8.33 mL butylbenzylamine. The mixture wasstirred 30 minutes at room temperature before adding 0.89 mL ofg-butyrolactone. The reaction was stirred overnight at room temperature,then quenched with 1N HCl to pH 2-3, and extracted with CH₂ Cl₂. Thecombined organics were washed with H₂ O and brine, and dried over Na₂SO₄. Filtration, evaporation, and flash chromatography with a 0-5%MeOH/CHCl₃ gradient provided 2.07 g of product.

¹ H-NMR (CDCl₃) δ 7.40-7.17 (m, 5H), 4.61 and 4.59 (s, 2H), 3.75 and3.65 (t, 2H), 3.38 and 3.21 (t, 2H), 2.58 and 2.47 (t, 2H), 2.00-1.80(m, 2H), 1.60-1.43 (m, 2H), 1.38-1.22 (m, 2H), 0.97-0.85 (2t, 3H).

Part B. Preparation of N-butyl, N-benzyl-4-(aminocarbonyl)propyl4-ethyl-2-propyl-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate

To a solution of 0.40 g4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylicacid in 50 mL anhydrous THF was added 0.27 g CDI in one portion. Afterstirring overnight at room temperature under N₂, there was added asolution of the sodium alkoxide of N-butyl,N-benzyl-4-hydroxy-butanamide (prepared from 0.48 g of the alcohol withNaH) in 5 mL THF. After 24 hours at room temperature, the reaction waspoured into cold brine and extracted with CH₂ Cl₂ /i-PrOH (4:1). Theorganic extract was dried (MgSO₄), filtered, evaporated, and purified byflash chromatography using 0-15% MeOH/CH₂ Cl₂ to give 0.16 g of product.

¹ H-NMR (CDCl₃) δ 13.5 (br s, 1H), 7.8 (m, 1H), 7.51-7.4 (m, 3H),7.38-7.10 (m, 4H), 7.10-7.08 (m, 1H), 7.08-7.00 (m, 2H), 6.82-6.77 (m,2H), 5.41 and 5.39 (s, 2H), 4.60 and 4.49 (s, 2H), 4.25 and 4.15 (t,2H), 3.37 and 3.18 (t, 2H), 2.85-2.68 (m, 2H), 2.55-2.45 (m, 2H), 2.40(t, 2H), 2.01-1.90 (2t, 2H), 1.65-1.40 (m, 2H), 1.28-1.20 (m, 4H),0.92-0.80 (2t, 6H).

EXAMPLE 9 ##STR87## Preparation of Preparation of N,N-dipentyl-4-(aminocarbonyl)propyl4-ethyl-2-propyl-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate##STR88## Part A. Preparation of N, N-dipentyl-4-hydroxy-butanamide

By employing the method described in Example 8, Part A, there wasobtained from 0.89 mL g-butyrolactone and 9.41 mL dipentylamine 2.51 gof pure product.

¹ H-NMR (CDCl₃) δ 3.99 (br s, 1H), 3.65 (t, 2H), 3.37-3.20 (m, 4H), 2.43(t, 2H), 1.95-1.83 (m, 2H), 1.62-1.43 (m, 4H), 1.40-1.20 (m, 8H),0.97-0.80 (2t, 6H).

Part B. Preparation of N, N-dipentyl-4-aminocarbonylpropyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate

By employing the method described in Example 8, Part B, there wasobtained from 0.47 g N, N-dipentyl-4-hydroxy-butanamide, 0.40 g4-ethyl-2-propyl-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid,and 0.27 g CDI 0.12 g of pure product.

¹ H-NMR (CDCl₃) δ 13.3 (br s, 1H), 7.81 (m, 1H), 7.55-7.38 (m, 3H),7.10-7.00 (m, 2H), 6.82-6.80 (m, 2H), 5.40 (s, 2H), 4.22 (t, 2H), 3.25(t, H), 3.19 (t, 2H), 2.84 (m, 2H), 2.50 (t, 2H), 2.40 (t, 2H), 2.01 (m,2H), 1.70-1.40 (m, 6H), 1.37-1.18 (m, 11H), 0.95-0.80 (m, 9H).

EXAMPLE 10 ##STR89## Preparation of 2-(N-Benzoylpiperidin-2-yl)ethyl1-[(2'-(n-butoxycarbonylaminosulfonyl)-3-fluorobiphenyl)methyl]-4-ethyl-2-propylimidazolecarboxylate.##STR90## Part A. Preparation of N-benzoyl-2-piperidineethanol

To a solution of benzoic anhydride (16.6 g, 73.5 mmol) and triethylamine(8.2 g, 81.1 mmol) in 150 mL of methylene chloride, was added2-piperidine-ethanol (10.0 g, 77.5 mmol). A slight exotherm was observedand the reaction mixture was stirred at ambient temperature overnight.The reaction mixture was washed in turn with 200 mL of 1N hydrochloricacid, 200 mL of saturated sodium bicarbonate, and 100 mL brine. Theorganic phase was dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum to give 14.0 g of a crude product. This waspurified by flash chromatography (silica gel, 100% ethyl acetate) toyield 9.47 g (55%) of product as a light amber oil. MS: m/e 234, [M+H]⁺; ¹ H NMR (300 MHz, CDCl₃): δ 1.50-1.75 (br m, 6H); 1.84-2.03 (br m,1H); 2.06 (complex t, 1H); 2.91 (br t, J=13 Hz, 1H); 3.47 (t, J=11.7 Hz,1H); 3.60-3.71 (br m, 2H); 4.15 (br s, 2H); 4.96 (br d, J=12 Hz, 1H);7.41 (br s, 5H). ##STR91##

Part B. Preparation of 1-(2-fluoro-4-iodobenzyl)-4-ethyl-2-propyl,1H-imidazole-5-carboxylic acid.

A solution of 30% hydrogen peroxide (5.2 mL, 50.9 mmol) in 80 mL oftetrahydrofuran was chilled in an ice bath. To this was added a solutionof sodium dihydrogen phosphate monohydrate (5.2 g, 37.7 mmol) in 50 mLof water followed by a solution of1-(2-fluoro-4-iodobenzyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxaldehyde(10 g, 25 mmol) in 80 mL of tetrahydrofuran. To this reaction mixture,was slowly added over a 30 minute period, a solution of 80% sodiumchlorite (5.65 g, 50 mmol) in 130 mL of water, maintaining the reactiontemperature between +5° and 10° C. The yellow reaction mixture was thenstirred at room temperature overnight. By the next day, the reactionmixture had become a turbid white solution, to which was added solidsodium sulfite (6.25 g, 49.6 mmol) followed by a solution of sodiumsulfite (23.4 g, 186 mmol) in 100 mL of water. The reaction mixture wasstirred for 30 minutes and its pH was adjusted to pH 12 with 3N sodiumhydroxide, dissolving any precipitated solids. The tetrahydrofuran wasstripped under vacuum and the aqueous residue was extracted with 250 mLof methylene chloride. The aqueous phase was stripped of any residualmethylene chloride under vacuum and filtered through celite. Thefiltrate was chilled in ice and the product precipitated with theaddition of 6N hydrochloric acid. The product was filtered, washed withice cold water, and dried overnight, yielding 6.88 g (66%) of product asa white solid. MS: m/e 417 [M+H]⁺ ; ¹ H NMR (300 MHz, DMSO-d₆): δ 0.87(t, J=7.3 Hz, 3H); 1.16 (t, J=7.3 Hz, 3H); 1.63 (m, 2H): 2.61 (t, J=7.7Hz, 2H); 2.81 (q, J=7.3 Hz, 2H); 5.52 (s, 2H); 6.33 (t, J=8.1 Hz, 1H);7.51 (d, J=8.1 Hz, 1H); 7.69 (d, J=9.5 Hz, 1H). ##STR92##

Part C. Preparation of 2-(N-Benzoylpiperidin-2-yl)ethyl1-[2-fluoro-4-iodophenyl)methyl]-4-ethyl-2-propylimidazolecarboxylate.

Oxalyl chloride (15 mL, 21.8 g, 172 mmol) was cautiously added to aflask containing the product from part B (1.5 g, 3.6, mmol), chilled ina ice bath. The cooling bath was removed and the reaction mixture washeated to reflux under nitrogen for 30 minutes. The excess oxalylchloride was stripped under vacuum and the solid residue was dissolvedin 15 mL dry methylene chloride. To the resulting solution was added asolution containing N-benzoyl-2-piperidineethanol (1.3 g, 5.5 mmol) andpyridine (1 mL, 0.98 g, 12 mmol) in 5 mL dry methylene chloride. Thereaction was refluxed under nitrogen for two hours and then stirred atroom temperature overnight. The reaction mixture was washed twice with40 mL of 1N hydrochloric acid, then four times with 25 mL saturatedsodium bicarbonate, and finally with 25 mL of brine. The organic layerwas dried over anhydrous magnesium sulfate, filtered and concentratedunder vacuum to give 2.56 g of crude product. This was purified by flashchromatography (silica gel, gradient: 50% hexane/50% ethyl acetyate-25%hexane/75% ethyl acetate) to yield 1.77 g (78%) of product as a glass.MS: m/e 632, [M+H]⁺. ##STR93##

Part D. Preparation of 2-(N-Benzoylpiperidin-2-yl)ethyl1-[(2'-(t-butylaminosulfonyl)-3-fluorobiphenyl)methyl]-4-ethyl-2-propylimidazolecarboxylate.

A mixture of the product from part C (1.0 g, 1.6 mmol),2-(t-butylamino)sulfonyl-phenyl boronic acid (0.55 g, 2.1 mmol),tetrabutylammonium bromide (0.05 g, 0.16 mmol), and potassium carbonate(0.60 g, 4.3 mmol) was suspended in 6 mL of toluene and 2 mL of water.The reaction mixture was degassed by evacuating and refilling withnitrogen. Tetrakistriphenylphosphine palladium(0) (0.1 g, 0.087 mmol)was added and the degassing procedure repeated. The reaction mixture wasrefluxed with efficient stirring overnight. The reaction mixture waspoured into a separatory funnel containing 25 mL of ethyl acetate andthe aqueous layer drained and discarded. The organic phase was washed inturn with 25 mL of water, two 25 mL portions of saturated sodiumbicarbonate, and 25 mL of brine. The organic phase was then dried overanhydrous magnesium sulfate, filtered and stripped under vacuum to give1.32 g of crude product. This was purified by flash chromatography(silica gel, gradient: 10% acetone/30% ethyl acetate/60% hexane-20%acetone/30% ethyl acetate/50% hexane) to yield 0.82 g (72%) of productas a glass. MS: m/e 703, [M+H]⁺. ##STR94##

Part E. Preparation of 2-(N-Benzoylpiperidin-2-yl)ethyl1-[(2'-aminosulfonyl)-3-fluorobiphenyl)methyl]-4-ethyl-2propylimidazolecarboxylate.

A solution of the product from part D (0.82 g, 1.1 mmol) in 35 mL oftrifluoroacetic acid was refluxed protected from moisture for 3 h. Thetrifluoroacetic acid was stripped under vacuum and the residue dissolvedin 50 mL of methylene chloride. This solution was washed with twoportions of 50 mL of saturated sodium bicarbonate and then with brine.The organic phase was dried over anhydrous magnesium sulfate, filtered,and stripped under vacuum to give 0.74 g (98%) of crude product as aglass. MS: m/e 661, [M+H]⁺. This product was sufficiently pure to use inthe next reaction. ##STR95##

Part F. Preparation of 2-(N-Benzoylpiperidin-2-yl)ethyl1-[(2'-(n-butoxycarbonylaminosulfonyl)-3-fluorobiphenyl)methyl]-4-ethyl-2-propylimidazolecarboxylate.

To a solution containing the product from part E (0.74 g, 1.1 mmol) and4-dimethylaminopyridine (0.63 g, 5.1 mmol) in a mixture of 5 mL ofpyridine and 50 mL of methylene chloride, was added n-butylchloroformate (0.65 g, 4.74 mmol) under a nitrogen atmosphere. Thereaction mixture was stirred overnight at room temperature, and thenwashed in turn with four 100 mL portions of 1N hydrochloric acid, 100 mLof saturated sodium bicarbonate, and 100 mL of brine. The organic phasewas dried over anhydrous magnesium sulfate, filtered and stripped undervacuum to give 0.88 g of crude product. This was purified by flashchromatography (silica gel, 0.5% acetic acid, 20% acetone, 30% ethylacetate, 50% hexane) to give 0.61 g (72%) of product as a white solidfoam. MS: m/e 761, [M+H]⁺.

EXAMPLE 11 ##STR96## Preparation of4-[(5-((2-benzoyl)phenylcarbonyloxymethyl)-4-chloro-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-isoamyloxycarbonylaminosulfonylbiphenyl,sodium salt. ##STR97## Part A. Preparation of1-[2'-(t-butylaminosulfonyl)-3-fluorobiphenyl-4-yl]methyl-4-chloro-2-n-propylimidazole-5-carboxaldehyde.

4-Chloro-2-n-propyl-imidazole-5-carboxaldehyde was prepared as describedin U.S. Pat. No. 4,760,083. The imidazole can then be converted to thetitle compound by using the methods of Example 1, Parts A, B, and C. NMR(CDCl₃) δ 9.77 (s,1H), 8.16 (d, 1H), 7.50 (m, 2H), 7.30 (m, 3H), 6.86(t, 1H), 5.63 (s, 2H), 3.55 (s, 1H), 2.65 (m, 2H), 1.79 (m, 2H), 1.00 (m12H). ##STR98##

Part B. Preparation of2'-(N-t-butyl)sulfonamido-4-[(4-chloro-5-hydroxymethyl-2-n-propylimidazol-1-yl)methyl]-3-fluorobiphenyl.

1-[2'-(t-Butylaminosulfonyl)-3-fluorobiphenyl-4-yl]methyl-4-chloro-2-n-propylimidazole-5-carboxaldehyde(3.49 g, 7.10 mmol) was dissolved in methanol (30 mL). Sodiumborohydride (0.32 g, 8.5 mmol) was added over 5 minutes. The reactionwas complete within minutes. The reaction was poured into water andextracted with ethyl acetate (3×). The solvent was dried (MgSO₄) and thesolvent removed in vacuo to yield 3.20 g of a tan powder. NMR (CDCl₃) δ8.18 (d, 1H), 7.55 (m, 2H), 7.30 (m, 3H), 6.78 (t, 1H), 5.49 (s, 2H),4.56 (d, 2H), 3.76 (s, 1H), 2.59 (m, 2H), 1.75 (m, 2H), 1.02 (s, 9H),0.98 (t, 3H). ##STR99##

Part C. Preparation of4-[(5-((2-benzoyl)phenylcarbonyloxy)methyl-4-chloro-2-n-propylimidazol-1-yl)methyl]-2'-(N-t-butyl)sulfonamido-3-fluorobiphenyl.

2-Benzoylbenzoic acid (0.23 g, 1.0 mmol), dicyclohexylcarbodiimide (0.21g, 1.0 mmol), dimethylaminopyridine (0.01 g, 0.1 mmol), and2'-(N-t-butyl)sulfonamido-4-[(4-chloro-5-hydroxymethyl-2-n-propylimidazol-1-yl)methyl]-3-fluorobiphenyl(0.50 g, 1.0 mmol) were all added to CH₂ Cl₂ (25 mL). The reaction wasstirred at room temperature for 72 h. The reaction was filtered. Thefiltrate was washed with water, 10% citric acid, water, dried (MgSO₄)and the solvent removed in vacuo to yield 0.72 g. NMR (CDCl₃) δ 8.16 (d,1H), 8.02 (d, 1H), 7.6-7.3 (m, 11H), 7.15 (t, 2H), 6.63 (t, 1H), 5.04(s, 2H), 4.93 (s, 2H), 3.67 (s, 1H), 2.55 (m, 2H), 1.70 (m 2H), 1.00 (m,12H). ##STR100##

Part D. Preparation of4-[(5-((2-benzoyl)phenylcarbonyloxy)methyl-4-chloro-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-sulfonamidobiphenyl.

4[(5-((2-Benzoyl)phenylcarbonyloxy)methyl-4-chloro-2-n-propylimidazol-1-yl)methyl]-2'-(N-t-butyl)sulfonamido-3-fluorobiphenyl(0.72 g, 1.0 mmol) was dissolved in trifluoroacetic acid (20 mL). Thereaction was heated to reflux for 2 hours. It then was stirred at roomtemperature overnight. The solvent was removed in vacuo. The residue wastaken up in CH₂ Cl₂. 10% Sodium bicarbonate was added until the aqueouswas neutral. The CH₂ Cl₂ layer was separated, dried, and the solventremoved in vacuo. Column chromatography using 50% ethyl acetate inhexane yielded 0.48 g. NMR (CDCl₃) δ 8.15 (d, 1H), 8.03 (d, 1H), 7.7-7.1(m, 13H), 6.67 (t, 1H), 5.03 (s, 2H), 4.91 (s, 2H), 4.48 (s, 2H), 2.55(m, 2H), 1.75 (m, 2H), 0.98 (t, 3H).

Part E. Preparation of4-[(5-((2-benzoyl)phenylcarbonyloxy)methyl-4-chloro-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-isoamyloxycarbonylaminosulfonylbiphenyl,sodium salt.

4-[(5-(2-Benzoyl)phenylcarbonyloxy)methyl-4-chloro-2-n-propylimidazol-1-yl)methyl]-3-fluoro-2'-sulfonamidobiphenyl(0.24 g, 0.37 mmol) and dimethylaminopyridine (0.28 g, 2.3 mmol) wereadded to a mixture of CH₂ Cl₂ (25 mL) and pyridine (1 mL).i-Amylchloroformate solution (2.25M in toluene, 1.0 mL, 2.3 mmol) wasadded to the reaction and it was stirred at room temperature for 48 h.The reaction was diluted with additional CH₂ Cl₂ and washed with 10%citric acid solution (3×). The solution was dried (MgSO₄) and thesolvent removed in vacuo. The material was then washed with hexane toyield 0.22 g of a solid. The product was titrated with 0.09M KOH and thewater was removed in vacuo. NMR (CDCl₃) δ 8.03 (m, 2H), 7.7-7.0 (m,13H), 6.65 (m, 1H), 4.91 (s, 2H), 4.79 (s, 2H), 3.49 (m, 2H), 2.57 (m,2H), 1.75 (m, 2H), 0.98 (t, 3H), 0.64 (d, 6H).

EXAMPLE 12 ##STR101## Preparation of1-((2'-((n-butyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazole##STR102## Part A. Preparation of1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-(1-(trimethylsilyloxy)ethenyl)-1H-imidazole

To a solution of 2.50 g (6.81 mmol) of1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-acetyl-1H-imidazole(67 R¹ =2-F, R² =4-Br, n=0; prepared using the procedures of Example 3,Parts A and B) in 80 mL anhydrous THF was added 7.59 mL trimethylsilyltriflate (40.8 mmol) under nitrogen at 22° C., followed by 11.38 mL(81.9 mmol) triethylamine. The mixture was stirred at 22° C. for 2.5hours and then diluted with 100 mL of anhydrous ethyl ether and quenchedwith 10 mL of saturated NaHCO₃ solution. The organic layer was washedwith saturated NaHCO₃ solution, dried over Na₂ SO₄, and filtered.Solvents were then removed under reduced pressure yield 2.69 g (90%) ofthe title compound as a brown oil, which was used without furtherpurification. ¹ H NMR (300 MHz, CDCl₃): δ 0.14 (s, 9H); 0.84 (t, 3H);1.16 (t, 3H); 1.68 (m, 2H); 2.41 (t, 2H); 2.56 (q, 2H); 4.30 (s, 1H);4.43 (s, 1H); 5.03 (s, 2H); 6.44 (t, 1H); 7.10 (m, 2H). ##STR103##

Part B. Preparation of1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-bromoacetyl-1H-imidazole

To 2.69 g (6.13 mmol) of1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-(1-(trimethylsilyloxy)ethenyl)-1H-imidazolein 100 mL THF at 0° C. was added 1.09 g (6.13 mmol) of NBS. Afterstirring for 30 min, the solution was poured into saturated NaHCO₃solution. The mixture was extracted with anhydrous ethyl ether, driedover Na₂ SO₄ and filtered. The filtrate was evaporated under reducedpressure to give 2.32 g (85%) of the title compound as a brown oil,which was used without further purification. ¹ H NMR (300 MHz, CDCl₃): δ0.96 (t, 3H); 1.42 (t, 3H); 1.76 (m, 2H); 2.46 (t, 2H); 3.02 (q, 2H);5.30 (s, 2H); 5.50 (s, 2H); 6.59 (t, 1H); 7.14 (m H). ##STR104##

Part C. Preparation of 2-phenoxyphenol

A solution of 23.4 g (74.9 mmol) of boron tribromide-dimethyl sulfidecomplex in 150 mL of 1,2-dichloroethane was added dropwise to 3.00 g(15.0 mmol) of 2-methoxyphenyl phenyl ether in 50 mL dichloroethane atroom temperature. The mixture was stirred at reflux overnight. 50 mL 3MNaOH was added to quench the reaction. After separation of layers, theorganic layer was extracted with 3×100 mL 3M NaOH. The combined aqueouslayer was acidified with conc. HCl, and the precipitated product wasextracted with 3×150 mL ethyl ether. After washing with brine solution,drying over MgSO₄, and filtering, solvents were evaporated under reducedpressure to give 2.30 g (82.4%) of an off-white solid, which was usedwithout further purification. ¹ H NMR (300 MHz, CDCl₃): δ 5.57 (s, 1H);6.81-6.90 (m, 2H); 7.01-7.07 (m, 4H); 7.12 (t, 1H, J=7.3 Hz); 7.31-7.38(m, 2H). ##STR105##

Part D. Preparation of1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazole

To a solution of 0.63 g (3.36 mmol) of 2-phenoxyphenol and 0.62 g (4.48mmol) of K₂ CO₃ in 75 mL acetone at ambient temperature was added 1.00 g(2.24 mmol) of1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-bromoacetyl-1H-imidazoleobtained from Part B of Example 11 in 25 mL acetone. After stirring atreflux overnight, the reaction mixture was poured into water andextracted with 3×100 mL ethyl acetate. The combined organic layers werewashed with brine, dried over MgSO₄, filtered, and the solventsevaporated under reduced pressure. The crude product was purified byflash column chromatography using 10-40% ethyl acetate in hexane, whichprovided 0.16 g (6.3%) of a clear oil after evaporation of solventsunder reduced pressure. ¹ H NMR (300 MHz, CDCl₃): δ 0.95 (t, 3H, J=7.3Hz); 1.29 (t, 3H, J =7.3 Hz); 1.66 (m, 2H); 2.60 (m, 2H); 2.81 (q, 2H,J=7.3 Hz); 5.00 (s, 2H); 6.38 (t, 1H, J=7.8 Hz); 6.89-7.29 (m, 10H).##STR106##

Part E. Preparation of1-((2'-(t-butylaminosulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazole

From 0.16 g (0.29 mmol) of1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazole,using 0.12 g (0.47 mmol) of 2-(t-butylamino)sulfonylphenyl boronic acid,0.12 g (0.86 mmol)potassium carbonate, 0.016 g (0.05 mmol)tetrabutylammonium bromide, 0.02 g (0.02 mmol)tetrakis(triphenylphosphine)palladium(0), with 1 mL of water and 2 mL oftoluene as solvent, 0.08 g (40%) of the title compound was obtainedfollowing the procedure of Example 3, Part F, after purification bypreparative TLC (silica gel; 20% acetone, 30% ethyl acetate, 50%hexane). ¹ H NMR (300 MHz, CDCl₃): δ 0.97 (m, 12H, overlapping t-butylsinglet and methyl triplet); 1.32 (t, 3H, J=7.3 Hz); 1.72 (m, 2H); 2.63(t, 2H, J=7.3 Hz); 2.83 (q, 2H, J=7.3 Hz); 3.57 (s, 1H); 5.06 (s, 2H);5.58 (s,2H); 6.61 (t, 1H, J=8.1 Hz); 6.87-7.09 (m, 7H); 7.12 (d, 1H,J=8.1 Hz); 7.23-7.29 (m,5H); 7.51 (m, 2H); 8.15 (d, 1H, J=7.7 Hz).##STR107##

Part F. Preparation of1-((2'-(aminosulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazole

From 0.08 g (0.12 mmol) of1-((2'-(t-butylaminosulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazolein 6 mL of trifluoroacetic acid, 0.08 g (100%) of the title compound wasobtained, following the precedure of Example 3, Part G, with a 5 hrreflux period. MS m/e=628, [M=H]⁺ ; ¹ H NMR (300 MHz, CDCl₃): δ 0.98 (t,3H, J =7.3 Hz); 1.33 (t, 3H, J=7.3 Hz); 2.66 (t, 2H, J=7.3 Hz); 2.83 (q,2H, J=7.3 Hz); 4.20 (br s, 2H); 5.04 (s, 2H); 5.56 (s,2H); 6.63 (t, 1H,J=7.8 Hz); 6.84-7.09 (m, 9H); 7.18 -7.29 (m,4H); 7.48-7.61 (m, 2H); 8.14(d, 1H, J=7.8 Hz). ##STR108## Part G. Preparation of1-((2'-((n-butyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-2-(n-proply)-4-ethyl-5-(2-(phenoxyl)acetyl-1H-imidazole.

From 0.08 g (0.13 mmol) of 1-((2'-(aminosulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazoleand using 0.10 g (0.82 mmol) of 4-N,N-dimehtylaminopyreidine, 100 ml,0.11 g (0.73 mmol) of n-butyl chloroformate, with 1 mL pyridine and 10mL methylene chloride as solvent, 0.05 g (54%) of title was obtainedfollowing the procedure of Example 3, Part H, with a 16 hr reaction timeand after purification by prep TLC (silica gel; 20% acetone, 30% ethylacetate, 50% hexane). MS m/e=728, [M=H]⁺ ; ¹ H NMR (300 MHz, CDCl₃)δ0.83(t, 3H, J=7.3 Hz); 0.98 (t, 3H, J=7.3 Hz); 1.18 (m.2H); 1.32 (t, 3H,J=7.3 Hz); 1.43 (m,2H); 1.73 (m,2H) 2.67 (t, 2H, J=7.7 Hz);2.82 (q, 2H,j=7.3 Hz); 3.98 (t, 2H, J=6.6 Hz);5.05 (s, 2H); 5.57 (s,2H); 6.59 (t,1H, j=7.7 Hz); 6.86-7.10 (m, 6H);7.16-7.33 (m,6H);7.54-7.66 (m,2H);8.25(d, 1H, J=7.7 Hz).

Compounds 13-488 in tables 1-5 can be prepared by the proceduresdescribed in examples 1-12 employing the approximately substitutedstarting materials.

                                      TABLE 1                                     __________________________________________________________________________     ##STR109##                                                                   Ex.                                                                           No.                                                                              R.sup.6                                                                            R.sup.8                                                                            R.sup.a             R.sup.13            R.sup.2                                                                              m.p.              __________________________________________________________________________    13 n-propyl a                                                                         ethyl                                                                               ##STR110##         CH.sub.3 O.sub.2 CNHSO.sub.2                                                                      H                        13a                                                                              n-propyl b                                                                         ethyl                                                                               ##STR111##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            H                        13b                                                                              n-propyl c                                                                         ethyl                                                                               ##STR112##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 H                        14 n-propyl d                                                                         ethyl                                                                               ##STR113##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            2-F                      15 n-propyl e                                                                         ethyl                                                                               ##STR114##         CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      16 n-propyl f                                                                         ethyl                                                                               ##STR115##         (CH.sub.3).sub.2 CHCH.sub.2 O.sub.2                                           CNHSO.sub.2         2-F                      17 n-propyl g                                                                         ethyl                                                                               ##STR116##         CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2         2-F                      18 n-propylethyl (M+H).sup.+ =756.3                                                         ##STR117##         CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2         2-Cl                     19 n-propyl h                                                                         ethyl                                                                               ##STR118##         CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2         2-F                      20 n-propylethyl (M+H).sup.+ =744.2                                                         ##STR119##         CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2         2-Cl                     21 n-propylethyl (M+H).sup.+ =710.3                                                         ##STR120##         CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2         2-Cl                     22 n-propyl i                                                                         ethyl                                                                               ##STR121##         CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      23 n-propyl j                                                                         ethyl                                                                               ##STR122##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      24 n-propyl k                                                                         ethyl                                                                               ##STR123##         CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      25 n-propyl l                                                                         ethyl                                                                               ##STR124##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      26 n-propyl m                                                                         ethyl                                                                               ##STR125##         CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      27 n-propyl n                                                                         ethyl                                                                               ##STR126##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      28 n-propyl o                                                                         ethyl                                                                               ##STR127##         CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      29 n-propyl p                                                                         ethyl                                                                               ##STR128##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      30 n-propyl q                                                                         ethyl                                                                               ##STR129##         CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      31 n-propyl r                                                                         ethyl                                                                               ##STR130##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      32 n-propyl s                                                                         ethyl                                                                               ##STR131##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      33 n-propyl t                                                                         ethyl                                                                               ##STR132##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      34 n-propyl u                                                                         ethyl                                                                               ##STR133##         (CH.sub.3 (CH.sub.2).sub.3- NHCONHSO.sub.                                     2                   2-F                      35 n-propyl v                                                                         Cl                                                                                  ##STR134##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      36 n-propylethyl (M+H).sup.+ =733.3                                                         ##STR135##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      37 n-propylethyl (M+H).sup.+ =719.2                                                         ##STR136##         CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2         2-F                      38 n-propylethyl (M+H).sup.+ =747.3                                                         ##STR137##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      39 n-propyl                                                                           ethyl                                                                               ##STR138##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F    w                 40 n-propyl                                                                           ethyl                                                                               ##STR139##         (CH.sub.3 (CH.sub.2).sub.3- NHCONHSO.sub.                                     2                   2-F                      41 n-propyl                                                                           ethyl                                                                               ##STR140##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F (M+H).sup.+ =                                                             744                      42 n-propyl                                                                           ethyl                                                                               ##STR141##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      43 n-propyl                                                                           ethyl                                                                               ##STR142##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-F                      44 n-propyl                                                                           ethyl                                                                               ##STR143##         (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      45 n-propyl                                                                           ethyl                                                                               ##STR144##         (CH.sub.3).sub.2 CHO.sub.2 CNHSO.sub.2                                                            2-F                      46 n-propyl                                                                           ethyl                                                                               ##STR145##         PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    2-F                      47 n-propyl                                                                           ethyl                                                                               ##STR146##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            2-F                      48 n-propyl                                                                           ethyl                                                                               ##STR147##         Ph(CH.sub.2).sub.3 O.sub.2 CNHSO.sub.2                                                            2-F                      49 n-propyl                                                                           ethyl                                                                               ##STR148##         Ph(CH.sub.2).sub.4 O.sub.2 CNHSO.sub.2                                                            2-F                      50 n-propyl                                                                           ethyl                                                                               ##STR149##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 H                        51 n-propyl                                                                           ethyl                                                                               ##STR150##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         H                        52 n-propyl                                                                           ethyl                                                                               ##STR151##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         H                        53 n-propyl                                                                           ethyl                                                                               ##STR152##         (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         H                        54 n-propyl                                                                           ethyl                                                                               ##STR153##         (CH.sub.3).sub.2 CHO.sub.2 CNHSO.sub.2                                                            H                        55 n-propyl                                                                           ethyl                                                                               ##STR154##         PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    H                        56 n-propyl                                                                           ethyl                                                                               ##STR155##         (CH.sub.3 (CH.sub.2).sub.3- NHCONHSO.sub.                                     2                   2-F                      57 n-propyl                                                                           ethyl                                                                               ##STR156##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      58 n-propyl                                                                           ethyl                                                                               ##STR157##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      59 n-propyl                                                                           ethyl                                                                               ##STR158##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-F                      60 n-propyl                                                                           ethyl                                                                               ##STR159##         (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      61 n-propyl                                                                           ethyl                                                                               ##STR160##         (CH.sub.3).sub.2 CHO.sub.2 CNHSO.sub.2                                                            2-F                      62 n-propyl                                                                           ethyl                                                                               ##STR161##         PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    2-F                      63 n-propyl                                                                           ethyl                                                                               ##STR162##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            2-F                      64 n-propyl                                                                           ethyl                                                                               ##STR163##         Ph(CH.sub.2).sub.3 O.sub.2 CNHSO.sub.2                                                            2-F                      65 n-propyl                                                                           ethyl                                                                               ##STR164##         Ph(CH.sub.2).sub.4 O.sub.2 CNHSO.sub.2                                                            2-F                      66 n-propyl                                                                           ethyl                                                                               ##STR165##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 H                        67 n-propyl                                                                           ethyl                                                                               ##STR166##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      68 n-propyl                                                                           ethyl                                                                               ##STR167##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      69 n-propyl                                                                           ethyl                                                                               ##STR168##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-F                      70 n-propyl                                                                           ethyl                                                                               ##STR169##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      71 n-propyl                                                                           ethyl                                                                               ##STR170##         CN.sub.4 H          H      x                 72 n-propyl                                                                           ethyl                                                                               ##STR171##         CN.sub.4 H          H 112.5-117.0            73 n-propyl                                                                           ethyl                                                                               ##STR172##         CN.sub.4 H          2-F    y                 74 n-propyl                                                                           ethyl                                                                               ##STR173##         CN.sub.4 H          H (M+H).sup.+ = 611      75 n-propyl                                                                           ethyl                                                                               ##STR174##         CN.sub.4 H          H      z                 76 n-propyl                                                                           ethyl                                                                               ##STR175##         CN.sub.4 H          H      aa                77 n-propyl                                                                           ethyl                                                                               ##STR176##         CN.sub.4 H          H      bb                78 n-propyl                                                                           ethyl                                                                               ##STR177##         CN.sub.4 H          H      bb                79 n-propyl                                                                           ethyl                                                                               ##STR178##         CN.sub.4 H          2-F    dd                80 n-propyl                                                                           ethyl                                                                               ##STR179##         PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    2-F                      81 n-propyl                                                                           ethyl                                                                               ##STR180##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            2-F                      82 n-propyl                                                                           ethyl                                                                               ##STR181##         Ph(CH.sub.2).sub.3 O.sub.2 CNHSO.sub.2                                                            2-F                      83 n-propyl                                                                           ethyl                                                                               ##STR182##         Ph(CH.sub.2).sub.4 O.sub.2 CNHSO.sub.2                                                            2-F                      84 n-propyl                                                                           ethyl                                                                               ##STR183##         (CH.sub.3 (CH.sub.2).sub.3- NHCONHSO.sub.                                     2                   2-F                      85 n-propyl                                                                           ethyl                                                                               ##STR184##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      86 n-propyl                                                                           ethyl                                                                               ##STR185##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      87 n-propyl                                                                           ethyl                                                                               ##STR186##         (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      88 n-propyl                                                                           ethyl                                                                               ##STR187##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 3-F (M+H).sup.+ =                                                             754                      89 n-propyl                                                                           ethyl                                                                               ##STR188##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-CH.sub.3 O             90 n-propyl                                                                           ethyl                                                                               ##STR189##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            2-CH.sub.3               91 n-propyl                                                                           ethyl                                                                               ##STR190##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 3-CH.sub.3 O             92 n-propyl                                                                           ethyl                                                                               ##STR191##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-NO.sub.2               93 n-propyl                                                                           ethyl                                                                               ##STR192##         (CH.sub.3 (CH.sub.2).sub.3- NHCONHSO.sub.                                     2                   2-CN                     94 n-propyl                                                                           ethyl                                                                               ##STR193##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 3-CH.sub.3 S             95 n-propyl                                                                           ethyl                                                                               ##STR194##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         3-CH.sub.3 SO.sub.2      96 n-propyl                                                                           ethyl                                                                               ##STR195##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         3-CH.sub.3 SO            97 n-propyl                                                                           ethyl                                                                               ##STR196##         (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-Br                     98 n-propyl                                                                           ethyl                                                                               ##STR197##         (CH.sub.3).sub.2 CHO.sub.2 CNHSO.sub.2                                                            3-I                      99 n-propyl                                                                           ethyl                                                                               ##STR198##         PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    2-F                      100                                                                              n-propyl                                                                           ethyl                                                                               ##STR199##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            H                        101                                                                              n-propyl                                                                           ethyl                                                                               ##STR200##         Ph(CH.sub.2).sub.3 O.sub.2 CNHSO.sub.2                                                            3-F                      102                                                                              n-propyl                                                                           ethyl                                                                               ##STR201##         Ph(CH.sub.2).sub.4 O.sub.2 CNHSO.sub.2                                                            3-F                      103                                                                              n-propyl                                                                           ethyl                                                                               ##STR202##         (CH.sub.3 (CH.sub.2).sub.3- NHCONHSO.sub.                                     2                   2-F                      104                                                                              n-propyl                                                                           ethyl                                                                               ##STR203##         2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                        O.sub.2 CNHSO.sub.2 2-Cl (M+H).sup.+ =                                                            796.6                    105                                                                              n-propyl                                                                           ethyl                                                                               ##STR204##         2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                        O.sub.2 CNHSO.sub.2 2-Cl                     106                                                                              n-propyl                                                                           ethyl                                                                               ##STR205##         2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                        O.sub.2 CNHSO.sub.2 2-Cl                     107                                                                              n-propyl                                                                           ethyl                                                                               ##STR206##         2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                        O.sub.2 CNHSO.sub.2 2-Cl                     108                                                                              n-propyl                                                                           ethyl                                                                               ##STR207##         2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                        O.sub.2 CNHSO.sub.2 2-Cl                     109                                                                              n-propyl                                                                           ethyl                                                                               ##STR208##         2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                        O.sub.2 CNHSO.sub.2 2-Cl                     110                                                                              n-propyl                                                                           ethyl                                                                               ##STR209##         2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                        O.sub.2 CNHSO.sub.2 2-Br                     111                                                                              n-propyl                                                                           ethyl                                                                               ##STR210##         2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                        O.sub.2 CNHSO.sub.2 2-Br                     112                                                                              n-propyl                                                                           ethyl                                                                               ##STR211##         2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                        O.sub.2 CNHSO.sub.2 2-Br                     113                                                                              n-propyl                                                                           ethyl                                                                               ##STR212##         (CH3)2CH(CH.sub.2).sub.2 O.sub.2                                              CNHSO.sub.2         2-F                      114                                                                              n-propyl                                                                           ethyl                                                                               ##STR213##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            3-F                      115                                                                              n-propyl                                                                           ethyl                                                                               ##STR214##         Ph(CH.sub.2).sub.3 O.sub.2 CNHSO.sub.2                                                            3-F                      116                                                                              n-propyl                                                                           ethyl                                                                               ##STR215##         Ph(CH.sub.2).sub.4 O.sub.2 CNHSO.sub.2                                                            2-F                      117                                                                              n-propyl                                                                           ethyl                                                                               ##STR216##         CH.sub.3 (CH.sub.2).sub.3- NHCONHSO.sub.2                                                         2-F                      118                                                                              n-propyl                                                                           ethyl                                                                               ##STR217##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      119                                                                              n-propyl                                                                           ethyl                                                                               ##STR218##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      120                                                                              n-propyl                                                                           ethyl                                                                               ##STR219##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-F                      121                                                                              n-propyl                                                                           ethyl                                                                               ##STR220##         (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      122                                                                              n-propyl                                                                           ethyl                                                                               ##STR221##         (CH.sub.3).sub.2 CHO.sub.2 CNHSO.sub.2                                                            2-F                      123                                                                              n-propyl                                                                           ethyl                                                                               ##STR222##         PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    2-F                      124                                                                              n-propyl                                                                           ethyl                                                                               ##STR223##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            3-F                      125                                                                              n-propyl                                                                           ethyl                                                                               ##STR224##         Ph(CH.sub.2).sub.3 O.sub.2 CNHSO.sub.2                                                            3-F                      126                                                                              n-propyl                                                                           ethyl                                                                               ##STR225##         Ph(CH.sub.2).sub.4 O.sub.2 CNHSO.sub.2                                                            2-F                      127                                                                              n-propyl                                                                           ethyl                                                                               ##STR226##         CH.sub.3 (CH.sub.2).sub.3- NHCONHSO.sub.2                                                         2-F                      128                                                                              n-propyl                                                                           ethyl                                                                               ##STR227##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      129                                                                              n-propyl                                                                           ethyl                                                                               ##STR228##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         3-F                      130                                                                              n-propyl                                                                           ethyl                                                                               ##STR229##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         3-F                      131                                                                              n-propyl                                                                           ethyl                                                                               ##STR230##         (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      132                                                                              n-propyl                                                                           ethyl                                                                               ##STR231##         (CH.sub.3).sub.2 CHO.sub.2 CNHSO.sub.2                                                            3-F                      133                                                                              n-propyl                                                                           ethyl                                                                               ##STR232##         PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    H                        134                                                                              n-propyl                                                                           ethyl                                                                               ##STR233##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            H                        135                                                                              n-propyl                                                                           ethyl                                                                               ##STR234##         Ph(CH.sub.2).sub.3 O.sub.2 CNHSO.sub.2                                                            H                        136                                                                              n-propyl                                                                           ethyl                                                                               ##STR235##         Ph(CH.sub.2).sub.4 O.sub.2 CNHSO.sub.2                                                            H                        137                                                                              n-propyl                                                                           ethyl                                                                               ##STR236##         CH.sub.3 (CH.sub.2).sub.3 -NHCONHSO.sub.2                                                         2-F                      138                                                                              n-propyl                                                                           ethyl                                                                               ##STR237##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      139                                                                              n-propyl                                                                           ethyl                                                                               ##STR238##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      140                                                                              n-propyl                                                                           ethyl                                                                               ##STR239##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-CH.sub.3 F             141                                                                              n-propyl                                                                           ethyl                                                                               ##STR240##         (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      142                                                                              n-propyl                                                                           ethyl                                                                               ##STR241##         (CH.sub.3).sub.2 CHO.sub.2 CNHSO.sub.2                                                            2-F                      143                                                                              n-propyl                                                                           ethyl                                                                               ##STR242##         PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    2-F                      144                                                                              n-propyl                                                                           ethyl                                                                               ##STR243##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            2-F                      145                                                                              n-propyl                                                                           ethyl                                                                               ##STR244##         Ph(CH.sub.2).sub.3 O.sub.2 CNHSO.sub.2                                                            2-Cl                     146                                                                              n-propyl                                                                           ethyl                                                                               ##STR245##         Ph(CH.sub.2).sub.4 O.sub.2 CNHSO.sub.2                                                            H                        147                                                                              n-propyl                                                                           ethyl                                                                               ##STR246##         CH.sub.3 (CH.sub.2).sub.3 -NHCONHSO.sub.2                                                         H                        148                                                                              n-propyl                                                                           ethyl                                                                               ##STR247##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-CH.sub.2 CH.sub.3      149                                                                              n-propyl                                                                           ethyl                                                                               ##STR248##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      150                                                                              n-propyl                                                                           ethyl                                                                               ##STR249##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         H                        151                                                                              n-propyl                                                                           ethyl                                                                               ##STR250##         (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-Br                     152                                                                              n-propyl                                                                           ethyl                                                                               ##STR251##         (CH.sub.3).sub.2 CHO.sub.2 CNHSO.sub.2                                                            3-CH(CH.sub.3).sub.2     153                                                                              n-propyl                                                                           ethyl                                                                               ##STR252##         PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    2-NO.sub.2               154                                                                              n-propyl                                                                           ethyl                                                                               ##STR253##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            H                        155                                                                              n-propyl                                                                           ethyl                                                                               ##STR254##         Ph(CH.sub.2).sub.3 O.sub.2 CNHSO.sub.2                                                            H                        156                                                                              n-propyl                                                                           ethyl                                                                               ##STR255##         Ph(CH.sub.2).sub.4 O.sub.2 CNHSO.sub.2                                                            H                        157                                                                              n-propyl                                                                           ethyl                                                                               ##STR256##         CH.sub.3 (CH.sub.2).sub.3- NHCONHSO.sub.2                                                         2-I                      158                                                                              n-propyl                                                                           ethyl                                                                               ##STR257##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 H                        159                                                                              n-propyl                                                                           ethyl                                                                               ##STR258##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         H                        160                                                                              n-propyl                                                                           ethyl                                                                               ##STR259##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         H                        161                                                                              n-propyl                                                                           ethyl                                                                               ##STR260##         (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      162                                                                              n-propyl                                                                           ethyl                                                                               ##STR261##         (CH.sub.3).sub.2 CHO.sub.2 CNHSO.sub.2                                                            2-F                      163                                                                              n-propyl                                                                           ethyl                                                                               ##STR262##         PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    2-F                      164                                                                              n-propyl                                                                           ethyl                                                                               ##STR263##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            2-F                      165                                                                              n-propyl                                                                           ethyl                                                                               ##STR264##         Ph(CH.sub.2).sub.3 O.sub.2 CNHSO.sub.2                                                            2-F                      166                                                                              n-propyl                                                                           ethyl                                                                               ##STR265##         Ph(CH.sub.2).sub.4 O.sub.2 CNHSO.sub.2                                                            H                        167                                                                              n-propyl                                                                           ethyl                                                                               ##STR266##         CH.sub.3 (CH.sub.2).sub.3- NHCONHSO.sub.2                                                         H                        168                                                                              n-propyl                                                                           ethyl                                                                               ##STR267##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 H                        169                                                                              n-propyl                                                                           ethyl                                                                               ##STR268##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      170                                                                              n-propyl                                                                           ethyl                                                                               ##STR269##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-F                      171                                                                              n-propyl                                                                           ethyl                                                                               ##STR270##         (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      172                                                                              n-propyl                                                                           ethyl                                                                               ##STR271##         (CH.sub.3).sub.2 CHO.sub.2 CNHSO.sub.2                                                            2-F                      173                                                                              n-propyl                                                                           ethyl                                                                               ##STR272##         PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    2-F                      174                                                                              n-propyl                                                                           ethyl                                                                               ##STR273##         Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            2-F                      175                                                                              n-propyl                                                                           ethyl                                                                               ##STR274##         Ph(CH.sub.2).sub.3 O.sub.2 CNHSO.sub.2                                                            H                        176                                                                              n-propyl                                                                           ethyl                                                                               ##STR275##         Ph(CH.sub.2).sub.4 O.sub.2 CNHSO.sub.2                                                            2-F                      177                                                                              n-propyl                                                                           ethyl                                                                               ##STR276##         CH.sub.3 (CH.sub.2).sub.3- NHCONHSO.sub.2                                                         2-F                      178                                                                              n-propyl                                                                           ethyl                                                                               ##STR277##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      179                                                                              n-propyl                                                                           ethyl                                                                               ##STR278##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         H                        180                                                                              n-propyl                                                                           ethyl                                                                               ##STR279##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-Cl                     181                                                                              ethyl                                                                              ethyl                                                                               ##STR280##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      182                                                                              ethyl                                                                              ethyl                                                                               ##STR281##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      183                                                                              ethyl                                                                              ethyl                                                                               ##STR282##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         H                        184                                                                              ethyl                                                                              ethyl                                                                               ##STR283##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         H                        185                                                                              ethyl                                                                              ethyl                                                                               ##STR284##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-F                      186                                                                              ethyl                                                                              ethyl                                                                               ##STR285##         (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-F                      187                                                                              n-propyl                                                                           ethyl                                                                               ##STR286##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F    ee                188                                                                              n-propyl                                                                           ethyl                                                                               ##STR287##         (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F    ff                189                                                                              n-propyl                                                                           ethyl                                                                               ##STR288##         (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F    gg                190                                                                              n-propyl                                                                           ethyl                                                                               ##STR289##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F (M+H).sup.+ =                                                             678                      191                                                                              n-propyl                                                                           ethyl                                                                               ##STR290##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      192                                                                              n-propyl                                                                           ethyl                                                                               ##STR291##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F    hh                193                                                                              n-propyl                                                                           SCH.sub.3                                                                           ##STR292##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      194                                                                              n-propyl                                                                           SOCH.sub.3                                                                          ##STR293##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      195                                                                              n-propyl                                                                           SO.sub.2 CH.sub.3                                                                   ##STR294##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      196                                                                              n-propyl                                                                           SCH.sub.3                                                                           ##STR295##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      197                                                                              n-propyl                                                                           SOCH.sub.3                                                                          ##STR296##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      198                                                                              n-propyl                                                                           SO.sub.2 CH.sub.3                                                                   ##STR297##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      199                                                                              n-propyl                                                                           ethyl                                                                               ##STR298##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      200                                                                              n-propyl                                                                           ethyl                                                                               ##STR299##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      201                                                                              n-propyl                                                                           ethyl                                                                               ##STR300##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      202                                                                              n-propyl                                                                           ethyl                                                                               ##STR301##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F (M+H).sup.+ =                                                             791                      203                                                                              n-propyl                                                                           ethyl                                                                               ##STR302##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      204                                                                              n-propyl                                                                           ethyl                                                                               ##STR303##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      205                                                                              n-propyl                                                                           ethyl                                                                               ##STR304##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      205                                                                              n-propyl                                                                           ethyl                                                                               ##STR305##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F (M+H).sup.+ =                                                             769.6                    206                                                                              n-propylethyl (M+H).sup.+ =769.5                                                         ##STR306##         (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      __________________________________________________________________________     a.sup.1 H NMR (K.sup.+  salt) (DMSOd.sub.6) δ 7.97-7.30 (m, 13H);       7.04 (d, 1H, J=8Hz); 6.78 (d, 2H, J=8Hz); 5.43 (s, 2H); 5.29 (s, 2H); 3.1     (s, 3H); 2.70-2.45 (m, 4H); 1.60 (t of q, 2H, J=7,7Hz); 0.99 (t, 3H,          J=7Hz); 0.87 (t, 3H, J=7Hz).                                                  b.sup.1 H NMR (K.sup.+  salt) (DMSOd.sub.6) δ 7.97-7.00 (m, 6H);        6.77 (d, 2H, J=8Hz); 5.41 (s, 2H); 5.28 (s, 2H); 3.74 (t, 2H, J=7Hz);         2.75-2.45 (m, 6H); 1.60 (t of q, 2H, J=7,7Hz); 0.98 (t, 3H, J=7Hz); 0.87      (t, 3H, J=7Hz).                                                               c.sup.1 H NMR (K.sup.+  salt) (DMSOd.sub.6) δ 8.14 (d, 1H, J=8Hz);      7.73 (d, 2H, J=8Hz); 7.60-7.42 (m, 3H); 7.42-7.20 (m, 8H); 7.08 (d, 1H,       J=8Hz); 6.80 (d, 2H, J=8Hz); 5.38 (s, 4H); 3.76 (t, 2H, J=7Hz); 2.63 (q,      2H, J=7Hz); 2.57 (t, 2H, J=7Hz); 1.66 (t of q, 2H, J=7,7Hz); 1.50-1.10 (m     3H); 1.05 (t, 3H, J=7Hz); 0.91 (t, 3H, J=7Hz).                                d.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.07 (d, 1H, J=8Hz);       7.74 (d, 2H, J=8Hz); 7.60-7.00 (m, 14H); 7.00 (d, 3H, J=8Hz); 6.31 (t, 1H     J=8Hz); 5.38 (s, 2H); 5.31 (s, 2H); 3.89 (t, 2H, J=7Hz); 2.75 (q, 4H,         J=7Hz); 2.45 (t, 2H, J=7Hz); 1.65 (t of q, 2H, J=7,7Hz); 1.06 (t, 3H,         J=7Hz); 0.90 (t, 3H, J=Hz).                                                   e.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.08 (d, 1H, J=8Hz);       7.75 (d, 2H, J=8Hz); 7.60-7.43 (, 3H); 7.43-6.95 (m, 9H); 6.36 (t, 1H,        J=8Hz); 5.40 (s, 2H); 5.37 (s, 2H); 3.63 (t, 2H, J=7Hz); 2.66 (q, 2H,         J=7Hz); 2.56 (t, 2H, J=7Hz); 1.64 (t of q, 2H, J=7,7Hz); 1.50-1.20 (m,        2H); 1.07 (t, 3H, J=7Hz); 0.91 (t, 3H, J=7Hz); 0.67 (t, 3H, J=7Hz).           f.sup.1 H NMR (CDCl.sub.3) δ 8.27 (d, 1H, J=8Hz); 7.77 (d, 2H,          J=8Hz); 7.70-7.00 (m, 2H); 6.73 (t, 1H, J=8Hz); 5.57 (s, 2H); 5.46 (s,        2H); 3.78 (d, 2H, J=7Hz); 3.00-2.75 (m, 4H); 1.90 (m, 3H); 1.20 (t, 3H,       J=7Hz); 1.00 (t, 3H, J=7Hz); 0.77 (d, 6H, J=7Hz).                             g.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.08 (d, 1H, J=8Hz);       7.75 (d, 2H, J=8Hz); 7.65-7.00 (m, 12H); 6.36 (t, 1H, J=8Hz); 5.41 (s,        2H); 5.36 (s, 2H); 3.68 (t, 2H, J=7Hz); 2.65 (q, 2H, J=7Hz); 2.56 (t, 2H,     J=7Hz); 1.66 (t of q, 2H, J=7,7Hz); 1.45-0.95 (m, 7H); 0.91 (t, 3H, J=&       Hz)                                                                           h.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.04 (d, 1H, J=8Hz);       7.41 (d, 1H, J=8Hz); 7.40-6.95 (m, 10H); 6.91 (d, 2H, J=8Hz); 6.84 (d, 1H     J=8Hz); 6.47 (t, 1H, J=8Hz); 5.38 (s, 2H); 5.28 (s, 2H); 3.68 (t, 2H,         J=7Hz); 2.82 (q, 2H, J=7Hz); 2.59 (t, 2H, J=7Hz); 1.71 (t of q, 2H, J=7,      Hz); 1.32 (t of t, 2H, J=7,7Hz); 1.25-1.00 (m, 5H); 0.94 (t, 3H, J=7Hz);      0.74 (t, 3H, J=7Hz).                                                          i.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.07 (d, 2H, J=8Hz);       7.85 (d, 2H, J=8Hz); 7.65-7.15 (m, 10H); 7.10 (d, 1H, J=8Hz); 7.05-6.90       (m, 1H); 6.50-6.35 (m, 1H); 5.51 (s, 2H); 5.37 (s, 2H); 3.70-3.55 (m, 2H)     2.74 (q, 2H, J=7Hz); 2.62 (t, 2H, J=7Hz); 1.73 (t of q, 2H, J=7,7Hz);         1.45-1.20 (m, 2H); 1.15 (t, 3H, J=7Hz); 0.96 (t, 3H, J=7Hz); 0.68 (t, 3H,     J=7Hz).                                                                       j.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.07 (d, 2H, J=8Hz);       7.85 (d, 2H, J=8Hz); 7.60-7.10 (m, 9H); 7.07 (d, 1H, J=8Hz); 6.96 (d, 1H,     J=8Hz); 6.41 (t, 1H, J=8Hz); 5.52 (s, 2H); 5.37 (s, 2H); 3.69 (t, 2H,         J=7Hz); 2.72 (q, 2H, J=7Hz); 2.62 (t, 2H, J=7Hz); 1.71 (t of q, 2H,           J=7,7Hz); 1.50-1.30 (m, 1H); 1.30-1.10 (m, 2H); 1.13 (t, 3H, J=7Hz); 0.96     (t, 3H, J=7Hz); 0.71 (d, 6H, J=7Hz).                                          k.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.05-7.90 (m, 1H);         7.50-6.90 (m, 12H); 6.46 (t, 1H, J=8Hz); 5.37 (s, 2H); 5.18 (s, 2H);          3.75-3.40 (m, 2H); 2.72 (q, 2H, J=7Hz); 2.60-2.40 (m, 2H); 1.75-1.50 (m,      2H); 1.50-1.20 (m, 2H); 1.20-1.00 (m, 3H); 0.95-0.75 (m, 3H); 0.75-0.60       (m, 3H).                                                                      l.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.05-7.90 (m, 1H);         7.50-6.90 (m, 12H); 6.60-6.40 (m, 1H); 5.42 (s, 2H); 5.25 (s, 2H);            3.90-3.60 (m, 2H); 2.77 (q, 2H, J=7Hz); 2.70-2.50 (m, 2H); 1.80-1.55 (m,      2H); 1.55-1.30 (m, 1H); 1.35-1.10 (m, 5H); 1.00-0.80 (m, 3H); 0.76 (d, 6H     J=7Hz).                                                                       m.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.00 (d, 1H, J=8Hz);       7.50-6.95 (m, 12H); 6.60-6.40 (m, 1H); 5.41 (s, 2H); 5.20 (s, 2H);            3.70-3.50 (m, 2H); 2.77 (q, 2H, J=7Hz); 2.59 (t, 2H, J=7Hz); 1.70 (m, 2H)     1.45-1.00 (m, 2H); 1.13 (t, 3H, J=7Hz); 0.94 (t, 3H, J=7Hz); 0.80-0.50 (m     3H).                                                                          n.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 7.97 (d, 1H, J=8Hz);       7.50-6.90 (m, 12H); 6.55-6.40 (m, 1H); 5.40 (s, 2H); 5.21 (s, 2H);            3.80-3.60 (m, 2H); 2.77 (q, 2H, J=7Hz); 2.60 (t, 2H, J=7Hz); 1.71-1.30 (m     1H); 1.30-1.00 (m, 2H); 1.13 (t, 3H, J=7Hz); 0.96 (t, 3H, J=7Hz); 0.75 (d     6H, J=7Hz).                                                                   o.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 7.98 (d, 1H, J=8Hz);       7.46 (d, 1H, J=8Hz); 7.45-7.10 (m, 11H); 7.07 (d, 1H, J=8Hz); 6.98 (d, 1H     J=8Hz); 6.46 (t, 1H, J=8Hz); 5.38 (s, 2H); 5.15 (s, 2H); 3.60 (t, 2H,         J=7Hz); 2.77 (q, 2H, J=7Hz); 2.59 (t, 2H, J=7Hz); 1.71 (t of q, 2H,           J=7,7Hz); 1.34 (t of q, 2H, J=7,7Hz); 1.15 (t, 3H, J=7Hz); 0.95 (t, 3H,       J=7Hz); 0.67 (t, 3H, J=7Hz).                                                  p.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 7.98 (d, 1H, J=8Hz);       7.46 (d, 1H, J=8Hz); 7.45-7.10 (m, 11H); 7.08 (d, 1H, J=8Hz); 7.01 (d, 1H     J=8Hz); 6.47 (t, 1H, J=8Hz); 5.38 (s, 2H); 5.17 (s, 2H); 3.73 (t, 2H,         J=7Hz); 2.77 (q, 2H, J=7Hz); 2.59 (t, 2H, J=7Hz); 1.80-1.60 (m, 2H);          1.50-1.30 (m, 1H); 1.30-1.10 (m, 2H); 1.15 (t, 3H, J=7Hz); 0.90 (t, 3H,       J=7Hz); 0.74 (d, 6H, J=7Hz).                                                  q.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 9.13 (s, 1H); 8.69 (s,     2H); 7.98 (s, 1H, J=8Hz); 7.60-7.40 (m, 3H); 7.34 (t, 1H, J=8Hz);             7.30-7.10 (m, 4H); 7.09 (d, 1H, J=8Hz); 7.02 (d, 1H, J=Hz); 6.45 (t, 1H,      J=8Hz); 6.45 (t, 1H, J=8Hz); 5.36 (s, 2H); 5.18 (s, 2H); 3.56 (t, 2H,         J=7Hz); 2.73 (q, 2H, J=7Hz); 2.60 (t, 2H, J=7Hz); 1.71 (t of q, 2H,           J=7,7Hz); 1.32 (t of q, 2H, J=7,7Hz); 1.13 (t, 3H, J=7Hz); 0.94 (t, 3H,       J=7Hz); 0.67 (t, 3H, J=7Hz).                                                  r.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.07 (d, 1H, J=8Hz);       7.45-7.15 (m, 5H); 7.14 (d, d, 1H, J=8Hz); 7.03 (d, 1H, J=8Hz); 6.93 (t,      1H, J=8Hz); 6.86 (d, 2H, J=8Hz); 6.47 (t, 1H, J=8Hz); 5.40 (s, 2H);           4.30-4.15 (m, 2H); 4.00-3.85 (m, 2H); 3.76 (t, 2H, J=7Hz); 2.89 (q, 2H,       J=7Hz); 2.64 (t, 2H, J=7Hz); 1.90-1.60 (m, 4H); 1.60-1.30 (m, 1H);            1.35-1.20 (m, 5H); 0.97 (t, 3H, J=7Hz); 0.77 (d, 6H, J=7Hz).                  s.sup.1 H NMR (CDCl.sub.3) δ 8.26 (d, 1H, J=8Hz); 7.64 (t, 1H,          J=8Hz); 7.57 (t, 1H, J=8Hz); 7.40-7.20 (m, 4H); 7.10 (d, 1H, J=11Hz);         7.05-6.80 (m, 4H); 6.64 (t, 1H, J=8Hz); 5.57 (s, 2H); 4.40 (t, 2H, J=7Hz)     4.15-3.95 (m, 4H); 2.91 (q, 2H, J=7Hz); 2.66 (t, 2H, J=7Hz); 2.17 (t of t     2H, J=7,7Hz); 1.74 (t of q, 2H, J=7,7Hz); 1.55-1.25 (m, 3H); 1.27 (t, 3H,     J=7Hz); 0.98 (t, 3H, J=7Hz); 0.82 (d, 6H, J=Hz).                              t.sup.1 H NMR (CDCl.sub.3) δ 8.19 (d, 1H. J=8Hz); 7.60-7.40 (m, 2H)     7.30-7.10 (m, 6H); 7.04 (d, 1H, J=11H); 6.90 (d, 1H, J=8Hz); 6.53 (t, 1H,     J=8Hz); 5.48 (s, 2H); 4.43 (s, 2H); 4.21 (t, 2H, J=7Hz); 3.93 (t, 2H,         J=7Hz); 3.46 (t, 2H, J=7Hz); 2.82 (q, 2H, J=7Hz); 2.59 (t, 2H, J=7Hz);        1.97 (t of t, 2H, J=7,7Hz); 1.66 (t of q, 2H, J=7,7Hz); 1.50-1.00 (m, 6H)     0.89 (t, 3H, J=7Hz); 0.74 (d, 6H, J=7Hz).                                     u.sup.1 H NMR (CDCl.sub.3) δ 8.16 (d, 1H, J=8Hz); 7.77 (d, 2H,          J=8Hz); 7.70-7.20 (m, 13H); 6.93 (d, 2H, J=8Hz); 5.96 (t, 1H, J=8Hz); 5.4     (s, 2H); 5.37 (s, 2H); 3.03 (q, 2H, J=7Hz); 2.74 (q, 2H, J=7Hz); 2.63 (t,     2H, J=7Hz); 1.69 (t of q, 2H, J=7,7Hz); 1.40-1.00 (m, 7H); 0.95 (t, 3H,       J=7Hz); 0.81 (t, 3H, J=7Hz).                                                  v.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.07 (d, 1H, J=8Hz);       7.75 (d, 2H, J=8Hz); 7.59 (d, 1H, J=8Hz); 7.60-7.00 (m, 11H); 6.37 (t, 1H     J=8Hz); 5.46 (s, 2H); 5.38 (s, 2H); 3.67 (t, 2H, J=7Hz); 2.56 (t, 2H,         J=7Hz); 1.63 (t of t, 2H, J=7,7Hz); 1.50-1.10 (m, 5H); 0.86 (t, 3H,           J=7Hz); 0.70 (d, 6H, J=7Hz).                                                  w.sup.1 H NMR (CDCl.sub.3) δ 8.18 (d, 1H, J=8Hz); 7.65-7.05 (m,         12H); 7.01 (d, 1H, J=10Hz); 6.91 (d, 1H, J=8Hz); 6.57 (t, 1H, J=8Hz); 5.5     (s, 2H); 5.33 (s, 2H); 3.96 (t, 2H, J=7Hz); 2.84 (q, 2H, J=7Hz); 2.58 (t,     2H, J=7Hz); 1.66 (q, 2H, J=7Hz); 1.50-1.20 (m, 3H); 1.16 (T, 3H, J=7HZ);      0.90 (T, 3H, J=7HZ); 0.74 (d, 6H, J=7Hz).                                     x.sup.1 H NMR (DMSOd.sub.6) δ 7.74 (s, 1H); 7.80-7.35 (m, 12H); 6.9     (d, 2H, J8Hz); 6.83 (d, 2H, J=8Hz); 5.48 (s, 2H); 5.29 (s, 2H); 2.72 (q       2H, J=7Hz); 2.52 (t, 2H, J=7Hz); 1.54 (t of q, 2H, J=7,7Hz); 1.05 (t, 3H,     J=7Hz); 0.83 (t, 3H, J=7Hz).                                                  y.sup.1 H NMR (CDCl.sub.3) δ 7.77 (d, 1H, J8Hz); 7.60 (t, 1H,           J=8Hz); 7.51 (t, 1H, J=8Hz); 7.45-7.00 (m, 6H); 7.09 (d, 6H, J=8Hz); 6.83     (d, 1H, J=11Hz); 6.72 (d, 1H, J=8Hz); 6.30 (t, 1H, J=8Hz); 5.41 (s, 2H);      5.12 (s, 2H); 2.70 (q, 2H, J=7Hz); 2.44 (t, 2H, J=7Hz); 1.60 (t of q, 2H,     J=7,7Hz); 1.04 (t, 3H, J=7Hz); 0.86 (t, 3H, J=8Hz).                           z.sup.1 H NMR (CDCl.sub.3) δ 7.85 (d, 1H, J=7Hz); 7.67 (d, 2H,          J=7Hz); 7.65-7.20 (m, 10H); 6.91 (d, 2H, J=7Hz); 6.55 (d, 2H, J=7Hz); 5.2     (s, 2H); 5.21 (s, 2H); 2.50-2.25 (m, 2H); 2.20-2.00 (m, 2H); 1.65-1.40 (m     2H); 0.90-0.60 (m, 6H).                                                       aa.sup.1 H NMR (CDCl.sub.3) δ 7.85-7.70 (m, 1H); 7.65-7.40 (m, 2H);     7.41 (d, 1H, J=8Hz); 7.40-6.80 (m, 11H); 6.75-6.60 (m, 2H); 5.38 (bs, 2H)     5.25-5.10 (m, 2H); 4.37 (s, 1H); 4.41 (s, 1H); 3.50-3.30 (m, 1H);             3.20-3.00 (m, 1H); 2.70-2.55 (m, 2H); 2.40-2.25 (m, 2H); 1.70-0.60 (m,        15H).                                                                         bb.sup.1 H NMR (CDCl.sub.3) δ 7.95-7.80 (m, 1H); 7.60-7.20 (m, 12H)     7.04 (d, 2H, J=8Hz); 6.67 (d, 2H, J=8Hz); 5.38 (s, 2H); 5.16 (s, 2H); 2.4     (q, 2H, J=7Hz); 2.15 (t, 2H, J=7Hz); 1.57 (t of q, 2H, J=7,7Hz); 0.90-0.7     (m, 6H).                                                                      cc.sup.1 H NMR (CDCl.sub.3) δ 7.85 (d, 1H, J=8Hz); 7.70-7.50 (m,        2H); 7.45-7.10 (m, 10H); 6.97 (d, 2H, J=8Hz); 6.54 (d, 2H, J=8Hz); 5.30       (s, 2H); 5.07 (s, 2H); 2.45-2.25 (m, 2H); 2.20-2.00 (m, 2H); 1.54 (t of q     2H, J=7,7Hz); 0.83 (t, 3H, J=7Hz); 0.73 (t, 3H, J=7Hz).                       dd.sup.1 H NMR (CDCl.sub.3) δ 7.83 (d, 1H, J=7Hz); 7.68 (d, 2H,         J=7Hz); 7.60-7.10 (m, 10H); 6.80-6.60 (m, 2H); 6.27 (t, 1H, J=7Hz); 5.30      (s, 4H); 2.50 (m, 2H); 2.33 (t, 2H, J=7Hz); 1.54 (t of q, 2H, J=7,7Hz);       0.95-0.60 (m, 6H).                                                            ee.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.01 (d, 1H, J=8Hz);      7.85-7.65 (m, 4H); 7.65-7.50 (m, 2H); 7.50-7.12 (m, 6H); 7.09 (d, 1H,         J=8Hz); 7.00 (d, 1H, J=8Hz); 6.48 (t, 1H, J=8Hz); 5.42 (s, 2H); 5.27 (s,      2H); 3.70 (t, 2H, J=7Hz); 2.84 (q, 2H, J=7Hz); 2.63 (t, 2H, J=7Hz); 1.73      (t of q, 2H, J=7,7Hz); 1.50-1.30 (m, 1H); 1.30-1.10 (m, 5H); 0.96 (t, 3H,     J=7Hz); 0.71 (d, 6H, J=7Hz).                                                  ff.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 7.93 (d, 1H, J=8Hz);      7.80-7.60 (m, 4H); 7.47 (t, 2H, J=8Hz); 7.45-7.05 (m, 6H); 7.01 (d, 1H,       J=8Hz); 6.93 (d, 1H, J=8Hz); 6.40 (t, 1H, J=8Hz); 5.34 (s, 2H); 5.19 (s,      2H); 3.53 (t, 2H, J=7Hz); 2.77 (q, 2H, J=7Hz); 2.57 (t, 2H, J=7Hz);           1.80-1.50 (m, 2H); 1.35-1.10 (m, 2H); 1.08 (t, 3H, J=7Hz); 0.88 (t, 3H,       J=7Hz); 0.60 (t, 3H, J=7Hz).                                                  gg.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.03 (d, 1H, J=8Hz);      7.40-7.15 (m, 5H); 7.10 (d, 1H, J=8Hz); 7.06 (d, 1H, J=8Hz); 6.95-6.80 (m     2H); 6.51 (t, 1H, J=8Hz); 5.44 (s, 2H); 5.25 (s, 2H); 3.97 (t, 2H, J=7Hz)     3.76 (t, 2H, J=7Hz); 2.82 (q, 2H, J=7Hz); 2.61 (t, 2H, J=7Hz); 1.90-1.55      (m, 5H); 1.55-1.35 (m, 1H); 1.28 (q, 2H, J=7Hz); 1.14 (t, 3H, J=7Hz); 0.9     (t, 3H, J=7Hz); 0.92 (d, 6H, J=7Hz); 0.77 (d, 6H, J=7Hz).                     hh.sup.1 H NMR (K.sup.+  salt) (CDCl.sub.3) δ 8.00 (d, 1H, J=8Hz);      7.80 (d, 2H, J=8Hz); 7.45 (t, 1H, J=8Hz); 7.40-7.05 (m, 5H); 7.05 (d, 1H,     J=8Hz); 7.00 (d, 1H, J=8Hz); 6.47 (t, 1H, J=8Hz); 5.37 (s, 2H); 4.18 (t,      2H, J=7Hz); 3.63 (t, 2H, J=7Hz); 2.97 (t, 2H, J=7Hz); 2.81 (q, 2H, J=7Hz)     2.55 (t, 2H, J=7Hz); 2.10-1.90 (m, 2H); 1.80-1.50 (m, 2H); 1.50-1.20 (m,      1H); 1.25-1.10 (m, 5H); 0.87 (t, 3H, J=7Hz); 0.66 (d, 6H, J=7Hz).        

The following examples in Table 2 can be synthesized by the proceduresdescribed in examples 1-12 and by methods familiar to one skilled in theart.

                                      TABLE 2                                     __________________________________________________________________________     ##STR307##                                                                   Ex                                                                            No.                                                                              R.sup.6                                                                            R.sup.8                                                                          R.sup.a           R.sup.b                                                                           R.sup.13            R2                       __________________________________________________________________________                                                         m.p.                     208                                                                              n-propyl                                                                           ethyl                                                                             ##STR308##       H   CH.sub.3 O.sub.2 CNHSO.sub.2                                                                      H                        209                                                                              n-propyl                                                                           ethyl                                                                             ##STR309##       H   Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            H                        210                                                                              n-propyl                                                                           ethyl                                                                             ##STR310##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 H                        211                                                                              n-propyl                                                                           ethyl                                                                             ##STR311##       H   Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            2-F                      212                                                                              n-propyl                                                                           ethyl                                                                             ##STR312##       H   CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      213                                                                              n-propyl                                                                           ethyl                                                                             ##STR313##       H   (CH.sub.3).sub.2 CHCH.sub.2 O.sub.2                                           CNHSO.sub.2         2-F                      214                                                                              n-propyl                                                                           ethyl                                                                             ##STR314##       H   CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2         2-F                      215                                                                              n-propyl                                                                           ethyl                                                                             ##STR315##       H   CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2         2-Cl                     216                                                                              n-propyl                                                                           ethyl                                                                             ##STR316##       H   CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2         2-F                      217                                                                              n-propyl                                                                           ethyl                                                                             ##STR317##       H   CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2         2-Cl                     218                                                                              n-propyl                                                                           ethyl                                                                             ##STR318##       H   CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2         2-Cl                     219                                                                              n-propyl                                                                           ethyl                                                                             ##STR319##       H   CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      220                                                                              n-propyl                                                                           ethyl                                                                             ##STR320##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      221                                                                              n-propyl                                                                           ethyl                                                                             ##STR321##       H   CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      222                                                                              n-propyl                                                                           ethyl                                                                             ##STR322##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      223                                                                              n-propyl                                                                           ethyl                                                                             ##STR323##       H   CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      224                                                                              n-propyl                                                                           ethyl                                                                             ##STR324##       H   CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F (M + H).sup.+  =                                                          757                      225                                                                              n-propyl                                                                           ethyl                                                                             ##STR325##       H   CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      226                                                                              n-propyl                                                                           ethyl                                                                             ##STR326##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      227                                                                              n-propyl                                                                           ethyl                                                                             ##STR327##       H   CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      228                                                                              n-propyl                                                                           ethyl                                                                             ##STR328##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      229                                                                              n-propyl                                                                           ethyl                                                                             ##STR329##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      230                                                                              n-propyl                                                                           ethyl                                                                             ##STR330##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      231                                                                              n-propyl                                                                           ethyl                                                                             ##STR331##       H   (CH.sub.3 (CH.sub.2).sub.3NHCONHSO.sub.2                                                          2-F                      232                                                                              n-propyl                                                                           Cl                                                                                ##STR332##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      233                                                                              n-propyl                                                                           ethyl                                                                             ##STR333##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      234                                                                              n-propyl                                                                           ethyl                                                                             ##STR334##       H   CH.sub.3 (CH.sub.2).sub.3NHCONHSO.sub.2                                                           2-F                      235                                                                              n-propyl                                                                           ethyl                                                                             ##STR335##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      236                                                                              n-propyl                                                                           ethyl                                                                             ##STR336##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      237                                                                              n-propyl                                                                           ethyl                                                                             ##STR337##       H   (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-F                      238                                                                              n-propyl                                                                           ethyl                                                                             ##STR338##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      239                                                                              n-propyl                                                                           ethyl                                                                             ##STR339##       H   (CH.sub.3).sub.2 CHO.sub.2 CNHSO.sub.2                                                            2-F                      240                                                                              n-propyl                                                                           ethyl                                                                             ##STR340##       H   PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    2-F                      241                                                                              n-propyl                                                                           ethyl                                                                             ##STR341##       H   Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.2                                                            2-F                      242                                                                              n-propyl                                                                           ethyl                                                                             ##STR342##       H   Ph(CH.sub.2).sub.3 O.sub.2 CNHSO.sub.2                                                            2-F                      243                                                                              n-propyl                                                                           ethyl                                                                             ##STR343##       H   Ph(CH.sub.2).sub.4 O.sub.2 CNHSO.sub.2                                                            2-F                      244                                                                              n-propyl                                                                           ethyl                                                                             ##STR344##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 H                        245                                                                              n-propyl                                                                           ethyl                                                                             ##STR345##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         H                        246                                                                              n-propyl                                                                           ethyl                                                                             ##STR346##       H   (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         H                        247                                                                              n-propyl                                                                           ethyl                                                                             ##STR347##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         H                        248                                                                              n-propyl                                                                           ethyl                                                                             ##STR348##       H   (CH.sub.3).sub.2 CHO.sub.2 CNHSO.sub.2                                                            H                        249                                                                              n-propyl                                                                           ethyl                                                                             ##STR349##       H   PhCH.sub.2 O.sub.2 CNHSO.sub.2                                                                    H                        250                                                                              n-propyl                                                                           ethyl                                                                             ##STR350##       H   CH.sub.3 (CH.sub.2).sub.3NHCONHSO.sub.2                                                           2-F                      251                                                                              n-propyl                                                                           ethyl                                                                             ##STR351##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      252                                                                              n-propyl                                                                           ethyl                                                                             ##STR352##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      253                                                                              ethyl                                                                              ethyl                                                                             ##STR353##       H   CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      254                                                                              ethyl                                                                              ethyl                                                                             ##STR354##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      255                                                                              ethyl                                                                              Cl                                                                                ##STR355##       H   CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      256                                                                              ethyl                                                                              Br                                                                                ##STR356##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      257                                                                              ethyl                                                                              C.sub.2 F.sub.6                                                                   ##STR357##       CH.sub.3                                                                          CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                             CNHSO.sub.2         2-F                      258                                                                              ethyl                                                                              ethyl                                                                             ##STR358##       n-butyl                                                                           (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 H                        259                                                                              n-propyl                                                                           ethyl                                                                             ##STR359##       H   CN.sub.4 H          2-F                      260                                                                              ethyl                                                                              ethyl                                                                             ##STR360##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2NHCONH                                     SO.sub.2            2-F                      261                                                                              n-propyl                                                                           ethyl                                                                             ##STR361##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      262                                                                              n-propyl                                                                           ethyl                                                                             ##STR362##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      263                                                                              n-propyl                                                                           ethyl                                                                             ##STR363##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      264                                                                              n-propyl                                                                           ethyl                                                                             ##STR364##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      265                                                                              n-propyl                                                                           ethyl                                                                             ##STR365##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      266                                                                              n-propyl                                                                           ethyl                                                                             ##STR366##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      267                                                                              n-propyl                                                                           ethyl                                                                             ##STR367##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      268                                                                              n-propyl                                                                           ethyl                                                                             ##STR368##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      269                                                                              n-propyl                                                                           ethyl                                                                             ##STR369##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      270                                                                              n-propyl                                                                           ethyl                                                                             ##STR370##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      271                                                                              n-propyl                                                                           ethyl                                                                             ##STR371##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      272                                                                              n-propyl                                                                           ethyl                                                                             ##STR372##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      273                                                                              n-propyl                                                                           ethyl                                                                             ##STR373##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      274                                                                              n-propyl                                                                           ethyl                                                                             ##STR374##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      275                                                                              n-propyl                                                                           ethyl                                                                             ##STR375##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      276                                                                              n-propyl                                                                           ethyl                                                                             ##STR376##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      277                                                                              n-propyl                                                                           ethyl                                                                             ##STR377##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      278                                                                              n-propyl                                                                           ethyl                                                                             ##STR378##       H   (CH.sub.3 (CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      279                                                                              n-propyl                                                                           ethyl                                                                             ##STR379##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      280                                                                              n-propyl                                                                           ethyl                                                                             ##STR380##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      281                                                                              n-propyl                                                                           ethyl                                                                             ##STR381##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      282                                                                              n-propyl                                                                           ethyl                                                                             ##STR382##       H   CN.sub.4 H          2-F                      283                                                                              n-propyl                                                                           ethyl                                                                             ##STR383##       CH.sub.3                                                                          (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      284                                                                              n-propyl                                                                           ethyl                                                                             ##STR384##       n-C.sub.3 H.sub.7                                                                 (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      285                                                                              n-propyl                                                                           ethyl                                                                             ##STR385##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F (M + H).sup.+  =                                                          717.4                    286                                                                              n-propyl                                                                           ethyl                                                                             ##STR386##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      287                                                                              n-propyl                                                                           ethyl                                                                             ##STR387##       H   (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-F (M + H).sup.+  =                                                          703.4                    288                                                                              n-propyl                                                                           ethyl                                                                             ##STR388##       H   CN.sub.4 H          2-F                      289                                                                              n-propyl                                                                           ethyl                                                                             ##STR389##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      290                                                                              n-propyl                                                                           ethyl                                                                             ##STR390##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      291                                                                              n-propyl                                                                           ethyl                                                                             ##STR391##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      292                                                                              n-propyl                                                                           ethyl                                                                             ##STR392##       H   CN.sub.4 H          2-F                      293                                                                              n-propyl                                                                           ethyl                                                                             ##STR393##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      294                                                                              n-propyl                                                                           ethyl                                                                             ##STR394##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      295                                                                              n-propyl                                                                           ethyl                                                                             ##STR395##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      296                                                                              n-propyl                                                                           ethyl                                                                             ##STR396##       H   CN.sub.4 H          2-F                      297                                                                              N-propyl                                                                           ethyl                                                                             ##STR397##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      298                                                                              n-propyl                                                                           ethyl                                                                             ##STR398##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      299                                                                              n-propyl                                                                           ethyl                                                                             ##STR399##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      300                                                                              n-propyl                                                                           ethyl                                                                             ##STR400##       H   CN.sub.4 H          2-F                      301                                                                              n-propyl                                                                           ethyl                                                                             ##STR401##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      302                                                                              n-propyl                                                                           ethyl                                                                             ##STR402##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      303                                                                              n-propyl                                                                           ethyl                                                                             ##STR403##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      304                                                                              n-propyl                                                                           ethyl                                                                             ##STR404##       H   CN.sub.4 H          2-F                      305                                                                              n-propyl                                                                           ethyl                                                                             ##STR405##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      306                                                                              n-propyl                                                                           ethyl                                                                             ##STR406##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      307                                                                              n-propyl                                                                           ethyl                                                                             ##STR407##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      308                                                                              n-propyl                                                                           ethyl                                                                             ##STR408##       H   CN.sub.4 H          2-F                      309                                                                              n-propyl                                                                           ethyl                                                                             ##STR409##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      310                                                                              n-propyl                                                                           ethyl                                                                             ##STR410##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      311                                                                              n-propyl                                                                           ethyl                                                                             ##STR411##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      312                                                                              n-propyl                                                                           ethyl                                                                             ##STR412##       H   CN.sub.4 H          2-F                      313                                                                              n-propyl                                                                           ethyl                                                                             ##STR413##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      314                                                                              n-propyl                                                                           ethyl                                                                             ##STR414##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      315                                                                              n-propyl                                                                           ethyl                                                                             ##STR415##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      316                                                                              n-propyl                                                                           ethyl                                                                             ##STR416##       H   CN.sub.4 H          2-F                      317                                                                              n-propyl                                                                           ethyl                                                                             ##STR417##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      318                                                                              n-propyl                                                                           ethyl                                                                             ##STR418##       H   (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2         2-F                      319                                                                              n-propyl                                                                           ethyl                                                                             ##STR419##       H   (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2         2-F                      320                                                                              n-propyl                                                                           ethyl                                                                             ##STR420##       H   CN.sub.4 H          2-F                      321                                                                              n-propyl                                                                           ethyl                                                                             ##STR421##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F (M + H).sup.+  =                                                          741                      322                                                                              n-propyl                                                                           ethyl                                                                             ##STR422##       H   (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-F (M + H).sup.+  =                                                          665.3                    323                                                                              n-propyl                                                                           ethyl                                                                             ##STR423##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F (M + H).sup.+                                                             =707                     324                                                                              n-propyl                                                                           ethyl                                                                             ##STR424##       H   (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2         2-F (M + H).sup.+  =                                                          693                      325                                                                              n-propyl                                                                           ethyl                                                                             ##STR425##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      326                                                                              n-propyl                                                                           ethyl                                                                             ##STR426##       H   (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2 2-F                      __________________________________________________________________________

The following examples in Table 3 can be synthesized by the proceduresdescribed in examples 1-12 and by methods familiar to one skilled in theart.

                                      TABLE 3                                     __________________________________________________________________________     ##STR427##                                                                   Ex                                                                            No.                                                                              R.sup.6                                                                            R.sup.8                                                                            R.sup.a                 R.sup.13           R.sup.2                                                                           m.p.              __________________________________________________________________________    327                                                                              n-propyl                                                                           ethyl                                                                               ##STR428##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   328                                                                              n-propyl                                                                           ethyl                                                                               ##STR429##             (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2        2-F                   329                                                                              n-propyl                                                                           ethyl                                                                               ##STR430##             (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2        2-F                   330                                                                              n-propyl                                                                           ethyl                                                                               ##STR431##             (CH.sub.3)(CH.sub.2).sub.4 O.sub.2                                            CNHSO.sub.2        2-F                   331                                                                              n-propyl                                                                           ethyl                                                                               ##STR432##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   332                                                                              n-propyl                                                                           ethyl                                                                               ##STR433##             (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2        2-F                   333                                                                              n-propyl                                                                           ethyl                                                                               ##STR434##             Ph(CH.sub.2).sub.2 O.sub.2 CNHSO.sub.                                         2                  2-F                   334                                                                              n-propyl                                                                           ethyl                                                                               ##STR435##             2'-(CH.sub.3)(CH.sub.2).sub.3                                                 O.sub.2 CNHSO.sub.2 5'-Cl                                                                        2-F                   335                                                                              n-propyl                                                                           ethyl                                                                               ##STR436##             (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2        2-F                   336                                                                              n-propyl                                                                           ethyl                                                                               ##STR437##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   337                                                                              n-propyl                                                                           ethyl                                                                               ##STR438##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   338                                                                              n-propyl                                                                           ethyl                                                                               ##STR439##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   339                                                                              n-propyl                                                                           ethyl                                                                               ##STR440##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   340                                                                              n-propyl                                                                           ethyl                                                                               ##STR441##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   341                                                                              n-propyl                                                                           ethyl                                                                               ##STR442##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   342                                                                              n-propyl                                                                           ethyl                                                                               ##STR443##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   343                                                                              n-propyl                                                                           ethyl                                                                               ##STR444##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   345                                                                              n-propyl                                                                           ethyl                                                                               ##STR445##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   346                                                                              n-propyl                                                                           ethyl                                                                               ##STR446##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   347                                                                              n-propyl                                                                           ethyl                                                                               ##STR447##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   348                                                                              n-propyl                                                                           ethyl                                                                               ##STR448##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   349                                                                              n-propyl                                                                           ethyl                                                                               ##STR449##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   350                                                                              n-propyl                                                                           ethyl                                                                               ##STR450##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   351                                                                              n-propyl                                                                           ethyl                                                                               ##STR451##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   352                                                                              n-propyl                                                                           ethyl                                                                               ##STR452##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   353                                                                              n-propyl                                                                           ethyl                                                                               ##STR453##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   354                                                                              n-propyl                                                                           ethyl                                                                               ##STR454##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   355                                                                              n-propyl                                                                           ethyl                                                                               ##STR455##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   356                                                                              n-propyl                                                                           ethyl                                                                               ##STR456##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           CHSO.sub.2         2-F                   357                                                                              n-propyl                                                                           ethyl                                                                               ##STR457##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   358                                                                              n-propyl                                                                           ethyl                                                                               ##STR458##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   359                                                                              n-propyl                                                                           ethyl                                                                               ##STR459##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   360                                                                              n-propyl                                                                           ethyl                                                                               ##STR460##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   361                                                                              n-propyl                                                                           ethyl                                                                               ##STR461##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   362                                                                              n-propyl                                                                           ethyl                                                                               ##STR462##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   363                                                                              n-propyl                                                                           ethyl                                                                               ##STR463##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   364                                                                              n-propyl                                                                           ethyl                                                                               ##STR464##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   365                                                                              n-propyl (M + H).sup.+                                                             ethyl                                                                               ##STR465##             (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2 M + H.sup.+  = 720.3                                                                 2-F                   366                                                                              n-propyl                                                                           ethyl                                                                               ##STR466##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   367                                                                              n-propyl                                                                           ethyl                                                                               ##STR467##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   368                                                                              n-propyl                                                                           ethyl                                                                               ##STR468##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   369                                                                              n-propyl                                                                           ethyl                                                                               ##STR469##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   370                                                                              n-propyl                                                                           ethyl                                                                               ##STR470##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   371                                                                              n-propyl                                                                           ethyl                                                                               ##STR471##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   372                                                                              n-propyl                                                                           ethyl                                                                               ##STR472##             CH.sub.3 (CH.sub.2).sub.3 OCNHSO.sub.                                         2                  2-F                   373                                                                              n-propyl                                                                           ethyl                                                                               ##STR473##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           OCNHSO.sub.2       2-F                   374                                                                              n-propyl                                                                           ethyl                                                                               ##STR474##             CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2        2-F                   375                                                                              n-propyl                                                                           ethyl                                                                               ##STR475##             CH.sub.3 (CH.sub.2).sub.2 OCNHSO.sub.                                         2                  2-F                   376                                                                              n-propyl                                                                           ethyl                                                                               ##STR476##             CH.sub.3 (CH.sub.2).sub.3 OCNHSO.sub.                                         2                  2-F                   377                                                                              n-propyl                                                                           ethyl                                                                               ##STR477##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           OCNHSO.sub.2       2-F                   378                                                                              n-propyl                                                                           ethyl                                                                               ##STR478##             CH.sub.3 (CH.sub.2).sub.3 OCNHSO.sub.                                         2                  2-F                   379                                                                              n-propyl                                                                           ethyl                                                                               ##STR479##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   380                                                                              n-propyl                                                                           ethyl                                                                               ##STR480##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           OCNHSO.sub.2       2-F                   381                                                                              n-Propyl                                                                           ethyl                                                                               ##STR481##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           OCNHSO.sub.2       2-F                   382                                                                              n-propylethyl (M + H).sup.+  = 726.5                                                     ##STR482##             (CH.sub.3)(CH.sub.2).sub.3 O.sub.2                                            CNHSO.sub.2        2-F                   383                                                                              n-propylethyl (M + H).sup.+  = 740.3                                                     ##STR483##             (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                              2-F                   384                                                                              n-propyl                                                                           ethyl                                                                               ##STR484##             (CH.sub.3).sub.2 CH(CH.sub.2)O.sub.2                                          CNHSO.sub.2 (M + H).sup.+  =                                                                     2-F.2                 385                                                                              n-propylethyl (M + H).sup.+  = 712.3                                                     ##STR485##             (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2        2-F                   386                                                                              ethyl                                                                              ethyl                                                                               ##STR486##             (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2        2-F                   387                                                                              n-butyl                                                                            Cl                                                                                  ##STR487##             (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2        2-F                   388                                                                              n-propyl                                                                           Br                                                                                  ##STR488##             (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2        2-F                   389                                                                              n-propyl                                                                           NO.sub.2                                                                            ##STR489##             (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2        2-F                   390                                                                              n-propyl                                                                           CF.sub.2 CF.sub.3                                                                   ##STR490##             (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2        2-F                   391                                                                              n-propyl                                                                           CH.sub.3                                                                            ##STR491##             (CH.sub.3)(CH.sub.2).sub.2 O.sub.2                                            CNHSO.sub.2        2-F                   392                                                                              n-propyl                                                                           ethyl                                                                               ##STR492##             (CH.sub.3)(CH.sub.2).sub.3 OCNHSO.sub                                         .2                 2-F                   393                                                                              n-propyl                                                                           ethyl                                                                               ##STR493##             (CH.sub.3)(CH.sub.2).sub.3 OCNHSO.sub                                         .2                 2-F                   394                                                                              n-propyl                                                                           ethyl                                                                               ##STR494##             (CH.sub.3)(CH.sub.2).sub.3 OCNHSO.sub                                         .2                 2-F                   395                                                                              n-propyl                                                                           ethyl                                                                               ##STR495##             CN.sub.4 H         2-F                   396                                                                              n-propyl                                                                           ethyl                                                                               ##STR496##             CN.sub.4 H         2-F                   397                                                                              n-propyl                                                                           ethyl                                                                               ##STR497##             (CH.sub.3)(CH.sub.2).sub.3 OCNHSO.sub                                         .2                 2-F                   398                                                                              n-propyl                                                                           ethyl                                                                               ##STR498##             (CH.sub.3)(CH.sub.2).sub.3 OCNHSO.sub                                         .2                 2-F                   __________________________________________________________________________

The following examples in Table 4 can be synthesized by the prodeduresdescribed in examples 1-12 and by the synthetic schemes described hereinand by methods familiar to one skilled in the art.

                                      TABLE 4                                     __________________________________________________________________________     ##STR499##                                                                   Ex                                                                            m.p.                                                                          No.    R.sup.6                                                                             R.sup.8                                                                             R.sup.a           R.sup.13          R.sup.2                                                                          X                   __________________________________________________________________________    399    n-propyl                                                                            Cl                                                                                   ##STR500##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  400    n-propyl                                                                            Br                                                                                   ##STR501##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  401    n-propyl                                                                            Br                                                                                   ##STR502##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  402    n-propyl                                                                            Cl                                                                                   ##STR503##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  403    n-propyl                                                                            Cl                                                                                   ##STR504##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  404    n-propyl                                                                            Cl                                                                                   ##STR505##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  405    n-propyl                                                                            Cl                                                                                   ##STR506##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  406    n-propyl                                                                            Cl                                                                                   ##STR507##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  407    n-propyl                                                                            Cl                                                                                   ##STR508##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  408 NH n-propyl                                                                            ethyl                                                                                ##STR509##       CN.sub.4 H        2-F                                                                              CO                  409    n-propyl                                                                            ethyl                                                                                ##STR510##       CN.sub.4 H        2-F                                                                              O                   410    n-propyl                                                                            ethyl                                                                                ##STR511##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              S                   411    n-propyl                                                                            ethyl                                                                                ##STR512##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              CH.sub.2            412    n-propyl                                                                            ethyl                                                                                ##STR513##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              CO                  413    n-propyl                                                                            ethyl                                                                                ##STR514##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              NMe                 414    n-propyl                                                                            ethyl                                                                                ##STR515##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              SO.sub.2            415    n-propyl                                                                            ethyl                                                                                ##STR516##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              SO                  416 NHCO                                                                             n-propyl                                                                            ethyl                                                                                ##STR517##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  417 OCH.sub.2                                                                        n-propyl                                                                            ethyl                                                                                ##STR518##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  418 CH.sub.2 O                                                                       n-propyl                                                                            ethyl                                                                                ##STR519##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  419 SCH.sub.2                                                                        n-propyl                                                                            ethyl                                                                                ##STR520##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  420 CH.sub.2 S                                                                       n-propyl                                                                            ethyl                                                                                ##STR521##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  421 NMeCH.sub.2                                                                      n-propyl                                                                            ethyl                                                                                ##STR522##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  422 NHSO.sub.2                                                                       n-propyl                                                                            ethyl                                                                                ##STR523##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  423 SO.sub.2 NH                                                                      n-propyl                                                                            ethyl                                                                                ##STR524##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  424 CHCH                                                                             n-propyl                                                                            ethyl                                                                                ##STR525##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  425 CH(OPh)                                                                          n-propyl                                                                            ethyl                                                                                ##STR526##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  426    n-propyl                                                                            ethyl                                                                                ##STR527##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                          ##STR528##                                                            427    n-propyl                                                                            ethyl                                                                                ##STR529##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              O                   428    n-propyl                                                                            ethyl                                                                                ##STR530##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              CO                  429 C(CH.sub.3).sub.2                                                                n-propyl                                                                            ethyl                                                                                ##STR531##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  430    n-propyl                                                                            ethyl                                                                                ##STR532##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  431    n-propyl                                                                            ethyl                                                                                ##STR533##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  432    n-propyl                                                                            ethyl                                                                                ##STR534##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  433    n-propyl                                                                            ethyl                                                                                ##STR535##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  434    n-propyl                                                                            ethyl                                                                                ##STR536##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  435    n-propyl                                                                            ethyl                                                                                ##STR537##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  436    n-propyl                                                                            ethyl                                                                                ##STR538##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  437    n-propyl                                                                            ethyl                                                                                ##STR539##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  438    n-propyl                                                                            ethyl                                                                                ##STR540##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  439    n-propyl                                                                            ethyl                                                                                ##STR541##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  440    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.2 NHCOPh                                                                (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  441    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.3 NHCOPh                                                                (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  442    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.4 NHCOPh                                                                (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  443    n-propyl                                                                            ethyl CO.sub.2 CH.sub.2 CONHPh                                                                        (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  444    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.2 CONHPh                                                                (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  445    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.3 CONHPh                                                                (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  446    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.4 CONHPh                                                                (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  447    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.2 NHCOPh                                                                (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             H  --                  448    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.3 NHCOPh                                                                (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             H  --                  449    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.4 NHCOPh                                                                (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             H  --                  450    n-propyl                                                                            ethyl CO.sub.2 CH.sub.2 CONHPh                                                                        (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             H  --                  451    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.2 CONHPh                                                                (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             H  --                  452    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.3 CONHPh                                                                (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             H  --                  453    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.4 CONHPh                                                                (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             H  --                  454    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.2 NHCOPh                                                                2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Cl                                                                             --                  455    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.3 NHCOPh                                                                2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Cl                                                                             --                  456    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.4 NHCOPh                                                                2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Cl                                                                             --                  457    n-propyl                                                                            ethyl CO.sub.2 CH.sub.2 CONHPh                                                                        2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Cl                                                                             --                  458    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.2 CONHPh                                                                2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Cl                                                                             --                  459    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.3 CONHPh                                                                2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Cl                                                                             --                  460    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.4 CONHPh                                                                2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Cl                                                                             --                  461    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.2 NHCOPh                                                                2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Br                                                                             --                  462    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.3 NHCOPh                                                                2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Br                                                                             --                  463    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.4 NHCOPh                                                                2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Br                                                                             --                  464    n-propyl                                                                            ethyl CO.sub.2 CH.sub.2 CONHPh                                                                        2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Br                                                                             --                  465    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.2 CONHPh                                                                2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Br                                                                             --                  466    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.3 CONHPh                                                                2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Br                                                                             --                  467    n-propyl                                                                            ethyl CO.sub.2 (CH.sub.2).sub.4 CONHPh                                                                2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Br                                                                             --                  468    n-propyl                                                                            cyclpropyl                                                                           ##STR542##       2'-(CH.sub.3).sub.2 CH(CH.sub.2).sub.                                         2 O.sub.2 CNHSO.sub.2                                                                           2-Cl                                                                             --                  469    n-propyl                                                                            Cl                                                                                   ##STR543##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  470    n-propyl                                                                            Cl                                                                                   ##STR544##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  471    n-propyl                                                                            Cl                                                                                   ##STR545##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  472    n-propyl                                                                            Cl                                                                                   ##STR546##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  473    n-propyl                                                                            Cl                                                                                   ##STR547##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  474    n-propyl                                                                            Cl                                                                                   ##STR548##       CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2       2-F                                                                              --                  475    n-propyl                                                                            Cl                                                                                   ##STR549##       CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2       2-F                                                                              --                  476    n-propyl                                                                            Cl                                                                                   ##STR550##       CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2       2-F                                                                              --                  477    n-propyl                                                                            Cl                                                                                   ##STR551##       CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2       2-F                                                                              --                  478    n-propyl                                                                            Cl                                                                                   ##STR552##       CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2       2-F                                                                              --                  479    n-propyl                                                                            Cl                                                                                   ##STR553##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  480    n-propyl                                                                            Cl                                                                                   ##STR554##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  481    n-propyl                                                                            Cl                                                                                   ##STR555##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  482    n-propyl                                                                            Cl                                                                                   ##STR556##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  483    n-propyl                                                                            Cl                                                                                   ##STR557##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                           O.sub.2 CNHSO.sub.2                                                                             2-F                                                                              --                  484    n-propyl                                                                            Cl                                                                                   ##STR558##       CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2       2-F                                                                              --                  485    n-propyl                                                                            Cl                                                                                   ##STR559##       CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2       2-F                                                                              --                  486    n-propyl                                                                            Cl                                                                                   ##STR560##       CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2       2-F                                                                              --                  487    n-propyl                                                                            Cl                                                                                   ##STR561##       CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2       2-F                                                                              --                  488    n-propyl                                                                            Cl                                                                                   ##STR562##       CH.sub.3 (CH.sub.2).sub.3 O.sub.2                                             CNHSO.sub.2       2-F                                                                              --                  __________________________________________________________________________

EXAMPLE 489 ##STR563## Preparation of1-(2'-((i-amyloxycarbonyl-amino)sulfonyl)-3-fluoro-(1,1'-biphenyl)'4-yl)methyl)-5-[2-(N-benzoyl-N-phenylamino)ethylcarbonyl-4-ethyl-2-propyl-1H-imidazole

Part A: Preparation of1-(2-fluoro-4-bromobenzyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxaldehyde##STR564##

this compound was prepared following the same method described in part Aof Example 3 (60% yield). ¹ HNMR (300 MHz, CDCl₃): δ0.95 (t, 3H, CH₃),1.32 (t, 3H, CH₃), 1.70 (m, 2H, CH₂), 2.60 (m, 2H, CH₂), 2.85 (q, H,CH₂), 5.52 (s, 2H, ArCH₂), 6.60 (t, 1H, ArH), 7.18 (d, 1H, ArH), 7.25(d, 1H, ArH), 9.75 (s, 1H, CHO). ##STR565##

Part B: Preparation of1-(2-fluoro-4-bromobenzyl)-4-ethyl-2-propyl-1H-imidazole-5-vinyl ketone

To a solution of1-(2-fluoro-4-bromobenzyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxaldehyde(21.58 g, 61.1 mmol) in THF (150 mL) was added vinylmagnesium bromide(92 mL of 1.0M solution in THF, 92.0 mmol) over 30 min. The reactionmixture was stirred at room temperature under N₂ for 1 h. It was thenquenched with 100 mL of 1N aqueous HCl. The mixture was extracted withCH₂ Cl₂, the organic solution was washed with H₂ O and brine, dried overMgSO₄ and concentrated to an orange oil. The resulting oil was dissolvedin CH₂ Cl₂ and manganese (IV) oxide (79.97 g, 920 mmol) was added. Theresulting mixture was stirred at room temperature under N₂ overnight.The mixture was filtered through celite and washed with CH₂ Cl₂. The CH₂Cl₂ solution was concentrated and chromatographed on silica gel with 1/1ethyl acetate/hexane to yield 20.4 g yellow oil. ¹ HNMR (300 MHz,CDCl₃): δ0.95 (t, 3H, CH₃), 1.30 (t, 3H, CH₃), 1.70 (m, 2H, CH₂), 2.60(m, 2H, CH₂), 2.88 (q, 2H, CH₂), 5.48 (s, 2H, ArCH₂), 5.80 (d, 1H, CH=),6.30 & 6.62 (d, 2H, =CH₂), 6.90 (t, 1H, ArH), 7.15 (d, 1H, ArH), 7.25(d, 1H, ArH). ##STR566##

Part C: Preparation of1-(2-fluoro-4-bromobenzyl)-5-[2-(N-phenylamino)ethylcarbonyl-4-ethyl-2-propyl-1H-imidazole

To a solution of1-(2-fluoro-4-bromobenzyl)-4-ethyl-2-propyl-1H-imidazole-5-vinyl ketone(2.06 g, 5.41 mmol) and triethylamine (2.50 mL, 16.5 mmol) in THF (100mL) was added aniline (1.50 mL, 16.5 mmol). The mixture was refluxedunder N₂ for 7 h. The solvent was removed in vacuo. The residue wasdissolved in EtOAc, and washed with H₂ O and brine. The organic solutionwas then dried over MgSO₄ and concentrated. the crude mixture waschromatographed on silica gel with 30-50% EtOAc/hexane to yield 2.03 goff-white solid (83%). ¹ HNMR (300 MHz, CDCl₃): δ0.97 (t, 3H, CH₃), 1.32(t, 3H, CH₃), 1.68 (m, 2H, CH₂), 2.58 (t, 2H, CH₂), 2.90 (q, 2H, CH₂),3.04 (t, 2H, CH₂), 3.49 (t, 2H, CH₂), 3.92 (s, 1H, NH), 5.49 (s, 2H,ArCH₂), 6.41 (t, 1H, ArH),6.57 (d, 2H, ArH), 6.71 (t, 1H, ArH), 7.15 (m,3H, ArH), 7.26 (m, 1H, ArH). ##STR567##

Part D: Preparation of1-(2-fluoro-4-bromobenzyl)-5-[2-(N-benzoyl-N-phenylamino)ethylcarbonyl-4-ethyl-2-propyl-1H-imidazole

To a solution of1-(2-fluoro-4-bromobenzyl)-5-[2-(N-phenylamino)ethylcarbonyl-4-ethyl-2-propyl-1H-imidazole(2.16 g, 4.96 mmol) and triethylamine (1.50 mL, 10.8 mmol) in THF (100mL) was added benzoyl chloride (1.20 mL, 10.3 mmol). The mixture wasrefluxed under N₂ for 1 h. The solvent was removed in vacuo. The residuewas dissolved in EtOAc, and washed with H₂ O, and then 1N NaOH andbrine. The organic solution was then dried over MgSO₄ and concentratedto a yellow oil (2.70 g, 94% yield). MS m/e 578.2,[M+H]⁺ ; ¹ HNMR (300MHz, CDCl₃): δ0.95 (t, 3H, CH₃), 1.27 (t, 3H, CH₃), 1.66 (m, 2H, CH₂),2.55 (t, 2H, CH₂), 2.90 (q, 2H, CH₂), 3.18 (t, 2H, CH₂), 4.22 (t, 2H,CH₂), 5.38 (s, 2H, ArCH₂), 6.40 (t, 1H, ArH),6.98 (d, 2H, ArH),7.10-7.30 (m, 5H, ArH), 7.55 (t, 2H, ArH), 7.70 (t, 1H, ArH), 8.15 (d,2H, ArH). ##STR568##

Part E: Preparation of1-((2'-((t-butylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-phenylamino)ethylcarbonyl-4-ethyl-2-propyl-1H-imidazole

1-(2-fluoro-4-bromobenzyl)-5-[2-(N-phenylamino)ethylcarbonyl-4-ethyl-2-propyl-1H-imidazole(2.20 g, 3.82 mmol), 2-(t-butylamino)sulfonylphenyl boronic acid (1.23g, 4.78 mmol), and soduim carbonate (5 mL of 2M aqueous solution), andtetrabutylammonium bromide (60 mg, 5%) were added together with 25 mL oftoluene. Tetrakis(triphenylphosphine) palladium(0) (0.22 g, 5%) wasadded. The mixture was refluxed under N₂ for 4 h. The solvent wasremoved in vacuo and the residue was partitioned between H₂ O and CH₂Cl₂. The aqueous layer was extracted with CH₂ Cl₂, and the combinedorganic solution was washed with brine, dried over MgSO₄ andconcentrated. The crude product was purified by flash columnchromatography (silica gel, 50% EtOAc/hexane) to give 1.66 g of paleyellow foam (61%). MS m/e 709.3, [M+H]⁺ ; ¹ H NMR (300 MHz, CDCl₃):δ0.95 (t, 3H, CH₃), 0.99 (t, 9H, CH₃), 1.30 (t, 3H, CH₃), 1.70 (m, 2H,CH₂), 2.60 (t, 2H, CH₂), 2.90 (q, 2H, CH₂), 3.22 (t, 2H, CH₂), 3.57 (s,1H, NH), 4.22 (t, 2H, CH₂), 5.50 (s, 2H, CH₂ Ar), 6.60 (t, 1H, ArH),7.02 (d, 3H, ArH), 7.10-7.30 (m, 10H, ArH), 7.50 (m, 2H, ArH), 8.15 (d,1H, ArH). ##STR569##

Part F: Preparation of1-((2'-(aminosulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-phenylamino)ethylcarbonyl-4-ethyl-2-propyl-1H-imidazole

1-((2'-((t-butylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-phenylamino)ethylcarbonyl-4-ethyl-2-propyl-1H-imidazole(1.66 g, 2.34 mmol) was refluxed with 25 mL of trifluoroacetic acidunder N₂ for 2.5 h. The solvent was removed in vacuo. The residue wasdissolved in CH₂ Cl₂, and washed with aqueous NaHCO₃ and brine. Theorganic solution was filtered through phase separator paper and thenconcentrated to a light yellow foam (1.39 g). MS m/e 695.2, [M+H]⁺ ; ¹ HNMR (300 MHz, CDCl₃): δ0.98 (t, 3H, CH₃), 1.27 (t, 3H, CH₃), 1.72 (m,2H, CH₂), 2.68 (t, 2H, CH₂), 2.88 (q, 2H, CH₂), 3.12 (t, 2H, CH₂), 4.20(t, 2H, CH₂), 4.40 (s, 2H, NH₂), 5.50 (s, 2H, CH₂ Ar), 6.63 (t, 1H,ArH), 7.00 (d, 3H, ArH), 7.10-7.30 (m, 11H, ArH), 7.50-7.60 (dd, 2H,ArH), 8.15 (d, 1H, ArH). ##STR570##

Part G: Preparation of1-((2'-((i-amyloxycarbonyl-amino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-phenylamino)ethylcarbonyl-4-ethyl-2-propyl-1H-imidazole

1-((2'-(aminosulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-phenylamino)ethylcarbonyl-4-ethyl-2-propyl-1H-imidazole(0.45 g, 0.69 mmol) was dissolved in 10 mL of CH₂ Cl₂. To the mixturewas added 4-N,N-dimethylaminopyridine (0.14 g, 1.15 mmol), pyridine (2mL), and isoamyl chloroformate (0.50 mL of 34% in toluene, 1.13 mmol).The reaction mixture was allowed to stir at room temperature under N₂overnight. The mixture was diluted with CH₂ Cl₂, and then washed with10% aqueous citric acid and brine. The organic solution was filteredthrough phase separator paper and concentrated. It was thenchromatographed on silica gel (eluted with 6:3:1 hexane/ethylacetate/acetone containing 0.1% HOAc) to give 0.29 g white foam.. MS m/e767.5, [M+H]⁺ ; ¹ H NMR (300 MHz, CDCl₃): δ0.77 (d, 6H, CH₃), 0.97 (t,3H, CH₃), 1.20 (t, 3H, CH₃), 1.31 (m, 2H, CH₂), 1.48 (m, 1H, CH), 1.70(m, 2H, CH₂), 2.59 (t, 2H, CH₂), 2.77 (q, 2H, CH₂), 3.06 (t, 2H, CH₂),3.79 (t, 2H, CH₂), 4.29 (t, 2H, CH₂), 5.24 (s, 2H, CH₂ Ar), 6.40 (t, 1H,ArH), 6.97 (d, 3H, ArH), 7.02 (m, 2H, ArH), 7.07-7.25 (m, 9H, ArH), 7.37(m, 2H, ArH), 8.16 (d, 1H, ArH).

EXAMPLE 490 ##STR571## Preparation of 1-((2'-((i-amloxycarbonyl-amino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-nicotinoyl-N-3-pyridinoamino)ethylcarbonyl-4-ethyl-2-propyl-1H-imidazole

The title compound was prepared by the same methods described in Example489 from the appropriate starting materials. MS (NH₃ DCl) 769, [M+H]⁺ ;¹ H NMR (300 MHz, CDC1₃): δ0.86 (d, 6H, CH₃), 0.97 (t, 3H, CH), 1.72(m,3H, CH₃), 2.52 (t, 3H, CH₃), 1.38 (m, 2H, CH₂), 1.50 (m, 1H, CH) 1.72(m, 2H, CH₂), 2.52 (t, 2H, CH₂), 2.98 (q, 2H, CH₂), 3.34 (br.s, 2H,CH₂), 4.00 (t, 2H, CH₂), 4.38 (br.s, 2H, CH₂), 5.40 (br.s, 2H, CH₂ AR),6.10 (t, 1H, ArH), 6.92 (d, 3H, ArH), 7.03-7.20 (m, 3H, ArH), 7.38 (dd,2H, ArH), 7.48-7.61 (m, 4H, ArH), 7.78 (d, 1H, ArH), 8.28 (m, 2H, ArH),8.33 (s, 1H, ArH), 83.45 (d, 1H, ArH).

EXAMPLE 491 ##STR572## Preparation of 1-((2'-((i-amyloxycarbonyl-amino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-[2-(N-butyryl-N-3-pyridinoamino)ethylcarbonyl-4-ethyl-2-propyl-1H-imidazole

The title compound was prepared by the same methods described in Example489 from the appropriate starting materials MS (FAB) 734.6, [M+H]⁺ ; ¹ HNMR (300 MHz, CDC1₃): δ0.77 (t, 3H, CH₃), 0.85 (d, 6H, CH₃), 0.94 (t,3H, CH₃), 1.34 (t, 3H, CH₃), 1.38-1.60 (m, 5H, CH & CH₂), 2.93 (q, 2H,CH₂), 3.21 (br.s, 2H, CH₂), 4.08 (t, 4H, CH₂), 5.50 (br.s, 2H, CH₂ Ar),6.19 (t, 1H, ArH), 7.03 (dd, 1H, ArH), 7.09 (dd, 3H, ArH), 7.22 (dd, 1H,ArH), 7.42 (m, 1H, ArH), 7.53-7.68 (m,3H, ArH), 7.71 (d, 1H, ArH), 8.31(dd, 1H, ArH), 8.44 (dd, 1H, ArH).

Compounds 489-696 in table 5 can be prepared by the procedure describedin Examples 489-491 employing appropriately substituted startingmaterials.

                  TABLE 5                                                         ______________________________________                                         ##STR573##                                                                   W     R.sup.2                                                                             R.sup.11a  R.sup.11b                                                                             R.sup.10                                                                             [M + H].sup.+                           ______________________________________                                        489   F     Ph         Ph      i-amyl 767                                     490   F     3-pyridine 3-pyridine                                                                            i-amyl 769                                     491   F     3-pyridine n-Pr    i-amyl 734                                     492   F     nPr        Ph      i-amyl                                         493   F     n-Bu       Ph      n-Pr                                           494   F     n-Bu       Ph      n-Bu   733                                     495   F     n-Bu       Ph      i-Bu                                           496   F     n-Bu       Ph      i-amyl                                         497   F     nPr        nPr     n-Pr                                           498   F     nPr        nPr     n-Bu   685                                     499   F     nPr        nPr     i-Bu                                           500   F     nPr        nPr     i-amyl                                         501   F     Ph         Ph      n-Pr   739                                     502   F     Ph         Ph      n-Bu   753                                     503   F     Ph         Ph      i-Bu                                           504   F     nPr        Ph      n-pentyl                                       505   F     Ph         n-Pr    n-Pr                                           506   F     Ph         n-Pr    n-Bu   719                                     507   F     Ph         n-Pr    i-Bu                                           508   F     Ph         n-Pr    i-amyl 733                                     509   F     2-pyridine 3-pyridine                                                                            n-Pr                                           510   F     2-pyridine 3-pyridine                                                                            n-Bu                                           511   F     2-pyridine 3-pyridine                                                                            i-Bu                                           512   F     2-pyridine 3-pyridine                                                                            i-amyl 769                                     513   F     2-pyridine 4-pyridine                                                                            n-Pr                                           514   F     2-pyridine 4-pyridine                                                                            n-Bu                                           515   F     2-pyridine 4-pyridine                                                                            i-Bu                                           516   F     2-pyridine 4-pyridine                                                                            i-amyl                                         517   F     3-pyridine 3-pyridine                                                                            n-Pr                                           518   F     3-pyridine 3-pyridine                                                                            n-Bu   765                                     519   F     3-pyridine 3-pyridine                                                                            i-Bu                                           520   F     nPr        Ph      n-Bu   719                                     521   F     3-pyridine 4-pyridine                                                                            n-Pr                                           522   F     3-pyridine 4-pyridine                                                                            n-Bu   755                                     523   F     3-pyridine 4-pyridine                                                                            i-Bu                                           524   F     3-pyridine 4-pyridine                                                                            i-amyl 769                                     525   F     4-pyridine 3-pyridine                                                                            n-Pr                                           526   F     4-pyridine 3-pyridine                                                                            n-Bu                                           527   F     4-pyridine 3-pyridine                                                                            i-Bu                                           528   F     4-pyridine 3-pyridine                                                                            i-amyl                                         529   F     4-pyridine 4-pyridine                                                                            n-Pr                                           530   F     4-pyridine 4-pyridine                                                                            n-Bu                                           531   F     4-pyridine 4-pyridine                                                                            i-Bu                                           532   F     4-pyridine 4-pyridine                                                                            i-amyl                                         533   F     Ph         3-pyridine                                                                            n-Pr                                           534   F     Ph         3-pyridine                                                                            n-Bu                                           535   F     Ph         3-pyridine                                                                            i-Bu                                           536   F     Ph         3-pyridine                                                                            i-amyl                                         537   F     Ph         4-pyridine                                                                            n-Pr                                           538   F     Ph         4-pyridine                                                                            n-Bu                                           539   F     Ph         4-pyridine                                                                            i-Bu                                           540   F     Ph         4-pyridine                                                                            i-amyl 768                                     541   F     2-pyridine Ph      n-Pr                                           542   F     2-pyridine Ph      n-Bu                                           543   F     2-pyridine Ph      i-Bu                                           544   F     2-pyridine Ph      i-amyl                                         545   F     2-pyridine n-Pr    n-Pr                                           546   F     2-pyridine n-Pr    n-Bu                                           547   F     2-pyridine n-Pr    i-Bu                                           548   F     2-pyridine n-Pr    i-amyl 733                                     549   F     3-pyridine Ph      n-Pr                                           550   F     3-pyridine Ph      n-Bu                                           551   F     3-pyridine Ph      i-Bu                                           552   F     3-pyridine Ph      i-amyl                                         553   F     3-pyridine n-Pr    n-Pr                                           554   F     3-pyridine n-Pr    n-Bu                                           555   F     3-pyridine n-Pr    i-Bu                                           556   F     3-pyridine i-Pr    i-amyl 734                                     557   F     4-pyridine Ph      n-Pr                                           558   F     4-pyridine Ph      n-BU                                           559   F     4-pyridine Ph      i-BU                                           560   F     4-pyridine Ph      i-amyl                                         561   F     4-pyridine n-Pr    n-Pr                                           562   F     4-pyridine n-Pr    n-Bu                                           563   F     4-pyridine n-Pr    i-Bu                                           564   F     4-pyridine n-Pr    1 -amyl                                        565   H     nPr        Ph      n-Pr                                           566   F     nPr        Ph      i-Bu                                           567   H     nPr        Ph      i-Bu                                           568   H     nPr        Ph      i-amyl                                         569   H     n-Bu       Ph      n-Pr                                           570   H     n-Bu       Ph      n-Bu                                           571   H     n-Bu       Ph      i-Bu                                           572   H     n-Bu       Ph      i-amyl                                         573   H     nPr        nPr     n-Pr                                           574   H     nPr        nPr     n-Bu                                           575   H     nPr        nPr     i-Bu                                           576   H     nPr        nPr     i-amyl                                         577   H     Ph         Ph      n-Pr                                           578   H     Ph         Ph      n-Bu                                           579   H     Ph         Ph      i-Bu                                           580   H     Ph         Ph      i-amyl                                         581   H     nPr        n-Bu    n-Pr                                           582   H     nPr        n-Bu    n-Bu                                           583   H     nPr        n-Bu    i-Bu                                           584   H     nPr        n-Bu    i-amyl                                         585   H     2-pyridine 3-pyridine                                                                            n-Pr                                           586   H     2-pyridine 3-pyridine                                                                            n-Bu                                           587   H     2-pyridine 3-pyridine                                                                            i-Bu                                           588   H     2-pyridine 3-pyridine                                                                            i-amyl                                         589   H     2-pyridine 4-pyridine                                                                            n-Pr                                           590   H     2-pyridine 4-pyridine                                                                            n-Bu                                           591   H     2-pyridine 4-pyridine                                                                            i-Bu                                           592   H     2-pyridine 4-pyridine                                                                            i-amyl                                         593   H     3-pyridine 3-pyridine                                                                            n-Pr                                           594   H     3-pyridine 3-pyridine                                                                            n-Bu                                           595   H     3-pyridine 3-pyridine                                                                            i-Bu                                           596   H     3-pyridine 3-pyridine                                                                            i-amyl 751                                     597   H     3-pyridine 4-pyridine                                                                            n-Pr                                           598   H     3-pyridine 4-pyridine                                                                            n-Bu                                           599   H     3-pyridine 4-pyridine                                                                            i-Bu                                           600   H     3-pyridine 4-pyridine                                                                            i-amyl                                         601   H     4-pyridine 3-pyridine                                                                            n-Pr                                           602   H     4-pyridine 3-pyridine                                                                            n-Bu                                           603   H     4-pyridine 3-pyridine                                                                            i-Bu                                           604   H     4-pyridine 3-pyridine                                                                            i-amyl                                         605   H     4-pyridine 4-pyridine                                                                            n-Pr                                           606   H     4-pyridine 4-pyridine                                                                            n-Bu                                           607   H     4-pyridine 4-pyridine                                                                            i-Bu                                           608   H     4-pyridine 4-pyridine                                                                            i-amyl                                         609   H     Ph         3-pyridine                                                                            n-Pr                                           610   H     Ph         3-pyridine                                                                            n-Bu                                           611   H     Ph         3-pyridine                                                                            i-Bu                                           612   H     Ph         3-pyridine                                                                            i-amyl                                         613   H     Ph         4-pyridine                                                                            n-Pr                                           614   H     Ph         4-pyridine                                                                            n-Bu                                           615   H     Ph         4-pyridine                                                                            i-Bu                                           616   H     Ph         4-pyridine                                                                            i-amyl                                         617   H     2-pyridine Ph      n-Pr                                           618   H     2-pyridine Ph      n-Bu                                           619   H     2-pyridine Ph      i-Bu                                           620   H     2-pyridine Ph      i-amyl                                         621   H     2-pyridine n-Pr    n-Pr                                           622   H     2-pyridine n-Pr    n-Bu                                           623   H     2-pyridine n-Pr    i-Bu                                           624   H     2-pyridine n-Pr    i-amyl                                         625   H     3-pyridine Ph      n-Pr                                           626   H     3-pyridine Ph      n-Bu                                           627   H     3-pyridine Ph      i-Bu                                           628   H     3-pyridine Ph      i-amyl                                         629   H     3-pyridine n-Pr    n-Pr                                           630   H     3-pyridine n-Pr    n-Bu                                           631   H     3-pyridine n-Pr    i-Bu                                           632   H     3-pyridine n-Pr    i-amyl 716                                     633   H     4-pyridine Ph      n-Pr                                           634   H     4-pyridine Ph      n-Bu                                           635   H     4-pyridine Ph      i-Bu                                           636   H     4-pyridine Ph      i-amyl                                         637   H     4-pyridine n-Pr    n-Pr                                           638   H     4-pyridine n-Pr    n-Bu                                           639   H     4-pyridine n-Pr    i-Bu                                           640   H     4-pyridine n-Pr    i-amyl                                         641   F     2-pyridine n-Bu    n-Pr                                           642   F     2-pyridine n-Bu    n-Bu                                           643   F     2-pyridine n-Bu    i-Bu                                           644   F     2-pyridine n-Bu    i-amyl                                         645   F     2-pyridine i-Pr    n-Pr                                           646   F     2-pyridine i-Pr    n-Bu                                           647   F     2-pyridine i-Pr    i-Bu                                           648   F     2-pyridine i-Pr    i-amyl                                         649   F     3-pyridine n-Bu    n-Pr                                           650   F     3-pyridine n-Bu    n-Bu                                           651   F     3-pyridine n-Bu    i-Bu                                           652   F     3-pyridine n-Bu    i-amyl                                         653   F     3-pyridine i-Pr    n-Pr                                           654   F     3-pyridine i-Pr    n-Bu                                           655   F     3-pyridine i-Pr    i-Bu                                           656   F     3-pyridine i-Pr    i-amyl                                         657   F     4-pyridine n-Bu    n-Pr                                           658   F     4-pyridine n-Bu    n-Bu                                           659   F     4-pyridine n-Bu    i-Bu                                           660   F     4-pyridine n-Bu    i-amyl                                         661   F     4-pyridine i-Pr    n-Pr                                           662   F     4-pyridine i-Pr    n-Bu                                           663   F     4-pyridine i-Pr    i-Bu                                           664   F     4-pyridine i-Pr    i-amyl                                         665   F     Ph         Me      n-Pr                                           666   F     Ph         Me      n-Bu                                           667   F     Ph         Me      i-Bu                                           668   F     Ph         Me      i-amyl                                         669   F     Ph         Et      n-Pr                                           670   F     Ph         Et      n-Bu                                           671   F     Ph         Et      i-Bu                                           672   F     Ph         Et      i-amyl                                         673   F     2-pyridine Me      n-Pr                                           674   F     2-pyridine Me      n-Bu                                           675   F     2-pyridine Me      i-Bu                                           676   F     2-pyridine Me      i-amyl                                         677   F     2-pyridine Et      n-Pr                                           678   F     2-pyridine Et      n-Bu                                           679   F     2-pyridine Et      i-Bu                                           680   F     2-pyridine Et      i-amyl                                         681   F     3-pyridine Me      n-Pr                                           682   F     3-pyridine Me      n-Bu                                           683   F     3-pyridine Me      i-Bu                                           684   F     3-pyridine Me      i-amyl                                         685   F     3-pyridine Et      n-Pr                                           686   F     3-pyridine Et      n-Bu                                           687   F     3-pyridine Et      i-Bu                                           688   F     3-pyridine Et      i-amyl 720                                     689   F     4-pyridine Me      n-Pr                                           690   F     4-pyridine Me      n-Bu                                           691   F     4-pyridine Me      i-Bu                                           692   F     4-pyridine Me      i-amyl                                         693   F     4-pyridine Et      n-Pr                                           694   F     4-pyridine Et      n-Bu                                           695   F     4-pyridine Et      i-Bu                                           696   F     4-pyridine Et      i-amyl                                         ______________________________________                                    

Utility

Angiotensin II (All) produces numerous biological responses (e.g.vasoconstriction) through stimulation of its receptors on cellmembranes. For the purpose of identifying compounds such as Allantagonists which am capable of interacting with All receptors, aligand-receptor binding assay was utilized.

DuP 753 and PD123177 were used as standards, and to block Angiotensin IIbinding to the AT₁ and AT₂ sites, respectively. DuP 753 was synthesizedaccording to the procedures described by Carini and Duncia (U.S. Pat.No. 5,138,069). PD123177 was prepared using the methods described byBlankely et al. (U.S. Pat. No. 4,812,462).

AT₁ site binding was determined in a rat adrenal cortical microsomepreparation or in a rat liver membrane preparation. Results for AT₁binding were similar in both assays. AT₂ site binding was determinedusing a rat adrenal medulla preparation. For the adrenal corticalmicrosome and adrenal medulla preparations, the method of Chiu, et al.(Receptor, 1, 33, 1990) was employed. For the liver membranepreparation, the method of Bauer et al. (Molecular Pharmacology, 39,579-585, 1991) was used, with the following changes: male Charles RiverCD rats were employed; the homogenation buffer consisted of a solutionof Trizma base (10 mM) and EDTA (5.0 mM) adjusted to pH 7.5 with 1N HCl;the binding buffer consisted of a solution of Trizma base (50 mM) andMgCl₂ 6H₂ O (5 mM) adjusted to pH 7.20 with 6N HCl; and the binding wasassessed using a 96 well plate format at 22° C. To illustrate theadrenal cortex assay, in brief, aliquots of a freshly preparedparticulate fraction of rat adrenal cortex were incubated with 0.15 nM[¹²⁵ I] AII and varying concentrations of potential AII antagonists in aTris buffer. After a 1 h incubation the reaction was terminated byaddition of cold assay buffer. The bound and free radioactivity wererapidly separated through glass-fiber filters, and the trappedradioactivity was quantitated by gamma counting. The inhibitoryconcentration (IC₅₀) of potential AII antagonists which gives 50%displacement of the total specifically bound [¹²⁵ I] AII is presented asa measure of the affinity of such compound for the AII receptor. AT₁site binding was determined in the presence of 10⁻⁶ M PD123177. AT₂ sitebinding was determined in the presence of 10⁻⁶ M DuP 753. IC₅₀ wasdetermined by displacement of [¹²⁵ I] AII from the receptor by the testcompound.

Using the assay method described above, the compounds of this inventionam found to exhibit an activity of at least IC₅₀ <100 nanomolar at boththe AT₁ and AT₂ receptors, thereby demonstrating and confirming theactivity of these compounds as effective AT₁ /AT₂ AII receptorantagonists.

The potential antihypertensive effects of the compounds of thisinvention may be demonstrated by administering the compounds to awakerats made hypertensive by ligation of the left renal artery (Cangiano,et al., J. Pharmacol. Exp. Ther., 208, 310, 1979). This procedureincreases blood pressure by increasing renin production with consequentelevation of AII levels. Compounds are administered intravenously viacannula in the jugular vein to give a cumulative dose of 10 mg/kg.Arterial blood pressure is continuously measured directly through acarotid artery cannula and recorded using a pressure transducer and apolygraph. Blood pressure levels after treatment are compared topretreatment levels to determine the antihypertensive effects of thecompounds.

Using the in vivo methodology described above, the compounds of thisinvention are found to exhibit an activity (intravenous) which is 10mg/kg or less, and/or an activity (oral) which is 100 mg/kg or less,thereby demonstrating and confirming the utility of these compounds aseffective agents in lowering blood pressure.

The compounds of this invention are useful in treating hypertension, andfor the treatment of hyperuricemia, primary and secondaryhyperaldosteronism, psoriasis, cardiac disorders such as acute andchronic congestive heart failure, angina pectoris, myocardialinfarction, systolic and diastolic dysfunction, cardiac myopathy, andcardiac hypertrophy and hyperplasia, esp. left ventricular hypertrophy;pulmonary disorders such as primary and secondary pulmonaryhypertension; vascular disorders such as atherosclerosis, restenosisafter vascular injury associated with e.g. angioplasty or bypasssurgery, vascular hypertrophy and hyperplasia, atheroma and Raynaud'sdisease; cerebrovascular disorders such as migraine, and ischemic andhemorragic stroke; renal disorders such as renal vascular hypertension,proteinuria of primary renal disease, end stage renal disease and renaltransplant therapy, glomerulonephritis, nephrotic syndrome, sclerodermaand glomerular sclerosis, and for enhancing renal blood flow; CNSdisorders such as impairment of cognitive function and memory loss,addiction, anxiety, bulimia, depression, epilepsy, pain, Parkinson'sdisease, psychosis, sleep disorders and tardive dyskinesia; oculardisorders such as macular degeneration and elevated intraocularpressure; gastrointestinal and bladder disorders; disorders associatedwith diabetes, such as diabetic angiopathy, nephropathy and retinopathy,and for delaying the onset of type II diabetes. The application of thecompounds of this invention for these and similar disorders will beapparent to those skilled in the art. The compounds of this inventionare also useful as diagnostic agents, to test the renin angiotensinsystem.

Patients in need of treatment for elevated intraocular pressure can betreated with compounds of this invention administered in the form oftypical pharmaceutical formulations such as tablets, capsules,injectables and the like as well as topical ocular formulations in theform of solutions, ointments, inserts, gels and the like. Pharmaceuticalformulations prepared to treat intraocular pressure would typicallycontain about 0.1% to 15% by weight, preferably 0.5% to 2% by weight, ofa compound of this invention. For this use, the compounds of thisinvention may also be used in combination with other medications for thetreatment of glaucoma including choline esterase inhibitors such asphysostigmine salicylate or demecarium bromide, parasympathomimeticagents such as pilocarpine nitrate, beta-adrenergic antagonists such astimolol maleate, adrenergic agonists such as epinephrine and carbonicanhydrase inhibitors such as MK-507.

In the management of hypertension and the clinical conditions notedabove, the compounds of this invention may be utilized with apharmaceutical carrier in compositions such as tablets, capsules orelixirs for oral administration, suppositories for rectaladministration, sterile solutions or suspensions for parenteral orintramuscular administration, and the like. The compounds of thisinvention can be administered to patients (animals and human) in need ofsuch treatment in dosages that will provide optimal pharmaceuticalefficacy. Although the dose will vary from patient to patient dependingupon the nature and severity of disease, the patient's weight, specialdiets being followed by a patient, concurrent medication, and otherfactors which those skilled in the art will recognize, the dosage rangewill generally be about 1 to 1000 mg per patient per day which can beadministered in single or multiple doses. Preferably, the dosage rangewill be about 5 to 500 mg per patient per day; more preferably about 5to 300 mg per patient per day.

Administration of a compound of this invention with a NSAID can preventrenal failure which sometimes results from administration of a NSAID.The compounds of this invention can also be administered in combinationwith other antihypertensives and/or diuretics. Administration of acompound of this invention with a diuretic, either as a stepwisecombined therapy (diuretic first) or as a physical mixture, enhances theantihypertensive effect of the compound. For example, the compounds ofthis invention can be given in combination with diuretics such ashydrochlorothiazide, chlorothiazide, chlorthalidone, methylclothiazide,furosemide, ethacrynic acid, triamterene, amiloride spironolactone andatriopeptin; calcium channel blockers, such as diltiazem, felodipine,nifedipine, amLodipine, nimodipine, isradipine, nitrendipine andverapamil; b-adrenergic antagonists such as timolol, atenolol,metoprolol, propanolol, nadolol and pindolol; angiotensin convertingenzyme inhibitors such as enalapril, lisinopril, captopril, ramipril,quinapril and zofenopril; renin inhibitors such as A-69729, FK 906 andFK 744; a-adrenergic antagonists such as prazosin, doxazosin, andterazosin; sympatholytic agents such as methyldopa, clonidine andguanabenz; atriopeptidase inhibitors (alone or with ANP) such asUK-79300; serotonin antagonists such as ketanserin; A₂ -adrenosinereceptor agonists such as CGS 22492C; potassium channel agonists such aspinacidil and cromakalim; and various other antihypertensive drugsincluding reserpine, minoxidil, guanethidine, hydralazine hydrochlorideand sodium nitroprusside as well as combinations of the above-nameddrugs. Combinations useful in the management of congestive heart failureinclude, in addition, compounds of this invention with cardiacstimulants such as dobutamine and xamoterol and phosphodiesteraseinhibitors including atarinone and milrinone.

What is claimed is:
 1. A compound of formula II: ##STR574## wherein: R²is independently(a) H, (b) halo, (c) C₁ -C₄ -alkyl; R³ is(a) H, or (b)halo; R⁶ is(a) C₁ -C₁₀ alkyl, (b) C₃ -C₁₀ alkenyl, or (c) C₃ -C₁₀alkynyl; R⁷ is(a) C₁ -C₆ -alkyl, (b) C₃ -C₆ -cycloalkyl, (c) aryl, or(d) benzyl, optionally substituted on the phenyl ring with 1-2substituents selected from the group consisting of halo, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy or --NO₂ ; R⁸ is(a) H, (b) halogen (c) aryl (d) C₁ -C₆-alkyl, optionally substituted withi) OR²⁵, ii) S(O)_(r) R¹⁰, iii) NR²³R²⁴, iv) NR²⁶ COR¹¹, v) NR²⁶ CO₂ R⁷, vi) NR²⁶ CONR²³ R²⁴, vii) OCONR²³R²⁴, viii) OCOR¹¹, ix) aryl (e) C₂ -C₆ -alkenyl, (f) --C₁ -C₄-alkyl-aryl, (h) C₁ -C₄ -alkoxy, (i) C_(v) F_(w) where v=1 to 3 and w=1to (2v+1), (j) --S(O)_(r) R¹⁰, (k) --S(O)₂ NR²³ R²⁴, (l) --CONR²³ R²⁴,(m) --COR⁷, or (n) --CO₂ R¹² ; R²⁵ is(a) H, (b) C₁ -C₆ alkyl, (c) aryl,(d) --(C₁ -C₄ -alkyl)-aryl, (e) C₃ -C₆ alkenyl, or (f) --(C₃ -C₆alkenyl)-aryl; R⁹ is(a) H, (b) C₁ -C₅ -alkyl, (c) aryl (d) --(C₁ -C₄-alkyl)-aryl, or (e) heteroaryl; R¹⁰ is(a) aryl, (b) C₃ -C₇ -cycloalkyl,(c) C₁ -C₄ -perfluoroalkyl, (d) C₁ -C₄ -alkyl, optionally substitutedwith a substituent selected from the group consisting of aryl as definedbelow, heteroaryl as defined below, --OH, --SH, C₁ -C₄ -alkyl, C₁ -C₄-alkoxy, C₁ -C₄ -alkylthio, --CF₃, halo, --NO₂, --CO₂ R¹², --NH₂, C₁ -C₄-alkylamino, C₁ -C₄ -dialkylamino, --PO₃ H₂, or (e) heteroaryl; R¹¹,R^(11a) and R^(11b) are independently(a) H, (b) C₁ -C₆ - alkyl, (c) C₃-C₆ -cycloalkyl, (d) aryl, (e) --(C₁ -C₅ -alkyl)-aryl, or (f)heteroaryl; R¹² is(a) H, (b) methyl, or (c) benzyl, optionallysubstituted on the phenyl ring with 1-2 substituents selected from thegroup consisting of halo, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy or --NO₂ ; R¹³is(a) --CO₂ H, (b) --CH₂ CO₂ H, (c) --C(CF₃)₂ OH, (d) --CONHNHSO₂ CF₃,(e) --CONHOR¹², (f) --CONHSO₂ R¹⁰, (g) --CONHSO₂ NHR⁹, (h) --C(OH)R⁹ PO₃H₂, (i) --NHCOCF₃, (j) --NHCONHSO₂ R¹⁰, (k) --NHPO₃ H₂, (l) --NHSO₂ R¹⁰,(m) --NHSO₂ NHCOR¹⁰, (n) --OPO₃ H₂, (o) --OSO₃ H, (p) --PO(OH)R⁹, (q)--PO₃ H₂, (r) --SO₃ H, (s) --SO₂ NHR⁹, (t) --SO₂ NHCOR¹⁰, (u) --SO₂NHCONHR⁹, (v) --SO₂ NHCO₂ R¹⁰, ##STR575## R⁴ is (a) CN, (b) NO₂, or (c)C₂ R¹¹ ; R¹⁶ is(a) H, (b) C₁ -C₆ -alkyl, or (c) benzyl, optionallysubstituted on the phenyl ring with 1-2 substituents selected from thegroup consisting of halo, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy or --NO₂ ; R²³and R²⁴ are, independently(a) H, (b) C₁ -C₆ -alkyl, (c) aryl, or (d)--(C₁ -C₄ -alkyl)-aryl, or R²³ and R²⁴ when taken together constitute apyrrolidine, piperidine or morpholine ring; R²⁶ is(a) H, (b) C₁ -C₄-alkyl, (c) aryl, or (d) arylmethyl; R²⁸ is(a) aryl, or (b) heteroaryl;R²⁹ is(a) --CHO, (b) --CONH₂, (c) --NHCHO, (d) --CO--(C₁ -C₆perfluoroalkyl), (e) --S(O)_(r) --(C₁ -C₆ perfluoroalkyl), (f) --O--(C₁-C₆ perfluoroalkyl), or (g) ---NR^(11a) --(C₁ -C₆ perfluoroalkyl); Eis(a) --(T)_(y) --(B)_(y) --X² --(B)_(y) --R²⁸ (b) --T--(B)_(y) --R²⁸(c) --(T)_(y) --(B)_(y) --X² --B, or (d) --T--(B)_(y) --R²⁹ --; L¹ is(a)--CO₂ -- (b) --CONR^(11a) -- (c) --NR^(11a) CO₂ -- (d) --NR^(11a)CONR^(11b) --; B is C₁ -C₆ alkyl; T is arylene or heteroarylene; X²is(a) --CO--, (b) --O--, (c) --S(O)_(r) --, (d) --(C₁ -C₄ -alkylene)--,(e) --NR^(11a) CONR^(11b) --, (f) --CONR^(11a) --, (g) --NR^(11a) CO--,(h) --SO₂ NR¹⁶ --, (i) --NR¹⁶ SO₂ --, (j) --CONR^(11a) SO₂ --, (k) --SO₂NR^(11a) CO--, (l) --SO₂ NR^(11a) CO₂ --, (m) --OCONR^(11a) SO₂ --, (n)--SO₂ NR^(11a) CONR^(11b) --, (o) --NR^(11a) CONR^(11b) SO₂ --, (p)--SO₂ NR^(11a) SO₂ --, (q) --CONR^(11a) SO₂ NR^(11b) --, or (r)--NR^(11a) SO₂ NR^(11b) CO--; n is 0 to 2; r is 0 to 2; y is 0 or1;wherein aryl is phenyl, biphenyl, or fluorenyl optionally substitutedwith one to three substituents selected from the group consisting of--OH, --SH, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, --CF₃, Cl, Br, F, --NO₂, --CO₂H, --CO₂ CH₃, --CO₂ -benzyl, --NH₂, --NH(C₁ -C₄ alkyl), --N(C₁ -C₄alkyl)₂ ; wherein heteroaryl is 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2-or 3-thienyl, 2-, 3- or 4-quinolinyl, or 1-, 3- or 4-isoquinolinyloptionally substituted with one to three substituents selected from thegroup consisting of --OH, --SH, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, --CF₃,halo, --NO₂, --CO₂ H, --CO₂ CH₃, --CO₂ -- benzyl, --NH₂, --NH(C₁ -C₄alkyl), --N(C₁ -C₄ alkyl)₂ ; wherein arylene is 1,2-phenyl, 1,3-phenyl,1,4-phenyl, 4,4'-biphenyl, 3,3'-biphenyl, and 2,2'-biphenyl optionallysubstituted with one to three substituents selected from the groupconsisting of --OH, --SH, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, --CF₃, halo,--NO₂, --CO₂ H, --CO₂ CH₃, --CO₂ -benzyl, --NH₂, --NH(C₁ -C₄ -alkyl),--N(C₁ -C₄ -alkyl)₂. and wherein heteroarylene is 2,3-pyridyl,3,4-pyridyl, 2,3-furyl, 3,4-furyl, 2,3-thiophenyl, 3,4-thiophenyl,2,3-quinolinyl, 3,4-quinolinyl and 1,4-isoquinolinyl optionallysubstituted with one to three substituents selected from the groupconsisting of --OH, --SH, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, --CF₃, halo,--NO₂, --CO₂ H, --CO₂ CH₃, --CO₂ -benzyl, --NH₂, --NH(C₁ -C₄ -alkyl),--N(C₁ -C₄ -alkyl)₂ ; or pharmaceutically acceptable salts of thesecompounds.
 2. A compound of claim 1 selected from the group consistingof:4-[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-n-butyloxycarbonylaminosulfonyl-1,1'-biphenyl,4-[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-((2-phenyl)ethyloxycarbonylaminosulfonyl)-1,1'-biphenyl,4-[[[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-2'-((2-phenyl)ethyloxycarbonylaminosulfonyl-1,1'-biphenyl,4-[[[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro2'-n-butyloxycarbonylaminosulfonyl-1,1'-biphenyl,4-[[[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-n-isoamyloxycarbonylaminosulfonyl-1,1'-biphenyl,4-[[[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-2'-n-isoamyloxycarbonylaminosulfonyl-1,1'-biphenyl,4-[[[((5-2(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-n-propyloxycarbonylaminosulfonyl-1,1'-biphenyl,4-[[[((5-(2-Isoamyloxybenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-n-butyloxycarbonylaminosulfonyl-1,1'-biphenyl,4-[[[((5-(2-Phenylaminocarbonyl)benzyloxycarbonyl-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-n-butyloxycarbonylaminosulfonyl-1,1'-biphenyl,4-[[[((5-(2-Benzoylbenzyloxycarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-(1H-tetrazol-5-yl)-1,1'-biphenyl,4-[[[((5-(2-trifluorophenyl)methylammocarbonyl)-4-ethyl-2-n-propyl)imidazol-1-yl)methyl]-3-fluoro-2'-isoamyloxycarbonylaminosulfonyl-1,1'-biphenyl,N-butyl, N-benzyl-2-(aminocarbonyl)ethynylmethyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate, N,N-diphenyl-2-(aminocarbonyl)ethynylmethyl 4-3thyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate, orN-phyenyl-2-(aminocarbonyl)ethyl4-ethyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate.
 3. A pharmaceutical composition comprising apharmaceutically suitable carrier and a compound selected from claim 1or claim
 2. 4. A method of treating hypertension in a warm-bloodedanimal comprising administering to said animal in need of such treatmentand effective amount of a compound selected from claim 1 or claim
 2. 5.A method of treating congestive heart failure in a warm-blooded animalcomprising administering to said animal in need of such treatment andeffective amount of a compound selected from claim 1 or claim 2.